RU2445952C2 - Stable compositions of digestive enzymes - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine, and represents a composition for treating and preventing a disorder related to digestive enzyme insufficiency, containing a set of coated particles; each said particle comprises a enteric-coated core wherein the core contains pancrelipase and the enteric coating contains 10-20 wt % of at least one enteric-coated polymer and 4-10 wt % of talc wherein said wt % are calculated from total weight of the coated particles and wherein the coated particles show pancrelipase enzymatic activity loss by no more than approximately 25% after 6 months of accelerated stability test.

EFFECT: invention provides enzyme activity stability.

47 cl, 14 ex, 35 tbl

Description

CROSS REFERENCE TO A RELATED APPLICATION

This application claims priority according to provisional application for US patent No. 60/902091, filed February 20, 2007, provisional application for US patent No. 60/902093, filed February 20, 2007. and provisional application for US patent No. 60/902092, filed February 20, 2007., the disclosure of each of which is incorporated herein by reference in its entirety for all purposes.

BACKGROUND

In cases of pancreatic insufficiency, pancrelipase and other products of pancreatic enzymes can be introduced to at least partially correct enzyme deficiency caused by various diseases affecting the pancreas, for example, pancreatitis, pancreatectomy, cystic fibrosis, and so on. The use of pancreatic enzymes in the treatment of pancreatic insufficiency is the main part of the treatment of patients with cystic fibrosis. Without these additives, patients experience severe malnutrition. If untreated, this malnutrition can be life threatening, especially in the case of infants.

The drug substance pancrelipase is mainly a combination of three classes of enzymes: lipase, protease and amylase, together with their various cofactors and coenzymes. These enzymes are naturally produced in the pancreas and are important for the digestion of fats, proteins and carbohydrates. Pancrelipase is usually obtained from porcine pancreas, although other sources can be used, for example, those described in US patents 6051220, 2004/0057944, 2001/0046493 and WO 2006044529, each of which is incorporated herein by reference. Enzymes catalyze the hydrolysis of fats to glycerol and fatty acids, starch to dextrin and sugars and protein to amino acids and their derivatives.

Pancreatic enzymes exhibit optimal activity in a near neutral or slightly alkaline environment. In the environment of the stomach, pancreatic enzymes can be inactivated, resulting in a loss of biological activity. Therefore, externally administered enzymes usually protect against inactivation in the stomach, and they remain intact while moving through the stomach into the duodenum. Although it is desirable to coat pancreatic enzymes, uncoated preparations are also on the market. Pancreatic lipases are most sensitive to inactivation in the stomach, and are also the most important enzymes in the treatment of malabsorption. To determine the stability of the enzyme composition containing a lipase, lipase activity is usually monitored.

After moving through the stomach, the enzymes should be released in the duodenum within 5-30 minutes, since digestion by pancreatic enzymes and absorption of metabolites mainly occur in the upper intestine, although digestion and absorption can take place anywhere in the digestive tract. Pancreatic enzymes are usually coated with an enteric polymer that protects the enzyme composition from the acidic environment of the stomach and then releases the enzyme in the gut.

Conventional pancreatic enzyme preparations are unstable and do not have a shelf life typical of approved pharmaceutical products for oral administration. The activity of pancreatic enzyme preparations is usually determined by the activity of lipase, which is one of the enzymes most sensitive to the loss of enzymatic activity during storage. In commercially available digestive enzyme compositions, the loss of lipase activity over time reaches approximately 35% or more. To compensate for the loss of enzymatic activity during storage and to ensure that the product has the activity indicated on the label at the end of its expiration date, manufacturers usually inject excess enzymes (5 to 60%) into pharmaceutical formulations and current US Pharmacopeia requirements for delayed-release pancrelipase capsules allow pancrelipase activity of not less than 90% and not more than 165% of the lipase activity indicated on the label.

In practice, this means that patients and prescribing doctors cannot accurately estimate the dosage, which in practice leads to an empirical selection of the right dosage for each new prescribed drug. Patients with exocrine pancreatic insufficiency rely on these drugs, which contain the enzymes necessary to properly digest food. If the label contains an inaccurate statement about the activity of a particular product, then the patient is at risk of receiving too large or too small a dose of the drug.

Accordingly, it would be desirable to obtain a stable composition of digestive enzymes capable of maintaining the necessary activity for the expected shelf life of the enzyme preparation without introducing into the dosage form an excess of the active substance.

SUMMARY OF THE INVENTION

The present invention relates to stable compositions of digestive enzymes, as well as to dosage forms and methods for producing stable enzyme compositions and dosage forms. More specifically, the present invention relates to enteric coated enzyme compositions and dosage forms with minimal loss of activity under typical storage conditions.

One embodiment of the present invention relates to a composition comprising at least one digestive enzyme, wherein the moisture content of the composition is about 3% or less.

In another embodiment, the composition of the present invention contains at least one digestive enzyme, wherein the water activity of the composition is about 0.6 or less.

In another embodiment, the composition of the present invention contains at least one stabilized digestive enzyme, where after 6 months of accelerated stability testing of at least one stabilized digestive enzyme, the activity loss does not exceed about 15%.

Another embodiment of the present invention relates to a dosage form, such as a tablet or capsule, filled with the composition of the present invention.

In yet another embodiment, the composition of the present invention further comprises at least one coated digestive enzyme, wherein the coating contains an enteric polymer and optionally at least one inorganic substance.

Another embodiment of the present invention relates to a package comprising a sealed container made of a waterproof material, a desiccant and at least one dosage form of the present invention, wherein the desiccant and at least one dosage form are in a sealed container.

Another embodiment of the present invention relates to a method for treating or preventing a disorder associated with a digestive enzyme deficiency, wherein the method comprises administering a composition of the present invention to a mammal in need thereof.

Another embodiment of the present invention relates to a method for producing a composition of the present invention. In one embodiment, the method comprises coating the particles of at least one digestive enzyme in an atmosphere having a moisture content of approximately 3.6 g of water per cubic meter or less, wherein the coating comprises an enteric polymer and at least one inorganic substance; as a result, a lot of particles with a delayed release are formed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention relates to a stabilized digestive enzyme composition. The term "stabilized digestive enzyme" means a digestive enzyme that retains significant enzymatic activity after prolonged storage. The term “digestive enzyme” means an enzyme in the digestive tract that breaks down food components so that the body can absorb or absorb them.

Non-limiting classes of digestive enzymes suitable for use in the present invention include lipases, amylases, and proteases. Non-limiting examples of digestive enzymes include pancrelipase (also called pancreatin), lipase, colipase, trypsin, chymotrypsin, chymotrypsin B, pancreatopeptidase, carboxypeptidase A, carboxypeptidase B, hydrolase esters of glycerol, phospholazinase, elastazoleazinase, elastase, , α-amylase, papain, chymopapain, glutenase, bromelain, ficin, β-amylase, cellulase, β-galactosidase, lactase, sucrase, isomaltase and mixtures thereof.

In one embodiment of the present invention, the stabilized digestive enzyme is a pancreatic enzyme. The term “pancreatic enzyme” as used herein refers to any type of enzyme present in pancreatic secretion, for example, amylase, lipase, protease, or mixtures thereof, or any extract of pancreatic origin having enzymatic activity, such as pancreatin . Pancreatic enzyme can be obtained by extraction from the pancreas, created artificially or obtained from sources other than the pancreas, such as microorganisms, plants or other animal tissues.

In another embodiment of the present invention, the stabilized digestive enzyme is pancrelipase. The terms "pancrelipase" or "pancreatin" mean a mixture of several types of enzymes, including amylase, lipase, and protease. Pancrelipase is commercially available, for example, from Nordmark Arzneimittel GmbH or Scientific Protein Laboratories LLC.

In one embodiment of the compositions of the present invention, the stabilized digestive enzyme comprises a lipase. The term "lipase" refers to an enzyme that catalyzes the hydrolysis of lipids to glycerol and simple fatty acids.

Examples of lipases suitable for the present invention include, but are not limited to, animal lipase (e.g., pork lipase), bacterial lipase (e.g., Pseudomonas lipase and / or Burkholderia lipase), fungal lipase, plant lipase, recombinant lipase (e.g., obtained by recombinant DNA technologies in a suitable host cell selected from any bacterial, yeast, fungal, plant host cells or insect or mammalian host cells in culture; or recombinant lipases, which contain an amino acid sequence homologous or substantially identical to a naturally occurring sequence; lipases encoded by a nucleic acid that is homologous or substantially identical to a naturally occurring nucleic acid that encodes a lipase, and so on), chemically modified lipase or mixtures thereof.

In another embodiment of the compositions of the present invention, the stabilized digestive enzyme contains amylase. The term “amylase” refers to glycoside hydrolyzing enzymes that break down starch, for example, α-amylases, β-amylases, γ-amylases, acid α-glycosidases, saliva amylases, such as ptyalin, and so on.

Amylases suitable for use in the compositions of the present invention include, but are not limited to, animal amylases, bacterial amylases, fungal amylases (e.g., Aspergillus amylase and preferably Aspergillus oryzae amylase), plant-based amylases, recombinant amylases (e.g., obtained by recombinant DNA technology) in a suitable host cell selected from any bacterial, yeast, fungal, plant host cells or insect or mammalian host cells in culture; and and recombinant amylases that contain an amino acid sequence homologous or substantially identical to a naturally occurring sequence; amylases encoded by a nucleic acid that is homologous or substantially identical to a naturally occurring nucleic acid encoding an amylase, etc.), chemically modified amylases or their mixtures.

In another embodiment of the compositions of the present invention, the stabilized digestive enzyme comprises a protease. The term “protease” generally refers to enzymes (eg, proteinases, peptidases or proteolytic enzymes) that break down the peptide bonds between amino acids of proteins. Proteases are typically identified by their catalytic type, for example, aspartic acid peptidases, cysteine (thiol) peptidases, metallopeptidases, serine peptidases, threonine peptidases, alkaline or semi-alkaline proteases, neutral and peptidases with unknown catalytic mechanisms.

Non-limiting examples of proteases suitable for use in the compositions or oral dosage forms of the present invention include serine proteases, threonine proteases, cysteine proteases, aspartic acid proteases (e.g. plasmepsin), metalloproteases, glutamine proteases and so on; in addition, proteases suitable for use in the compositions or oral dosage forms of the present invention include, but are not limited to, animal proteases, bacterial proteases, fungal proteases (e.g., Aspergillus melleus protease), plant proteases, recombinant proteases (e.g., obtained by recombinant DNA technology in a suitable host cell selected from any bacterial, yeast, fungal, plant host or insect or mammalian host cells cultured; or recombinant proteases that contain an amino acid sequence homologous or substantially identical to a naturally occurring sequence of proteases encoded by a nucleic acid that is homologous or substantially identical to a naturally occurring nucleic acid encoding a protease, and so on), chemically modified proteases or mixtures thereof.

Compositions or oral dosage forms of the present invention may contain one lipase or more (i.e., one lipase or two lipases or more), one amylase or more (i.e. one amylase or two amylases or more), one protease or more (i.e. one protease or two proteases or more), mixtures of one lipase or more with one or more amylases, mixtures of one lipase or more with one protease or more, mixtures of one amylase or more with one protease or more, or mixtures of one lipase or more with one amylase or more and more meas or more.

In one embodiment, the digestive enzyme is a porcine pancreatic extract containing various lipases (e.g., lipase, colipase, phospholipase A2, cholesterol esterase), proteases (e.g., trypsin, chymotrypsin, carboxypeptidase A and B, elastase, kininogenase, trypsin inhibitor), amylases and optionally nucleases (ribonuclease, deoxyribonuclease). In another embodiment, the digestive enzyme is substantially similar to human pancreatic juice. In yet another embodiment, the digestive enzyme is pancrelipase corresponding to the United States Pharmacopeia. In yet another embodiment, the digestive enzyme is ESP pancrelipase with lipase activity of 69-120 PIECES of USP / mg, amylase activity of 216 PIECES of USP / mg or more, protease activity of 264 PIECES of USP / mg and a total protease activity of 264 PIECES of USP / mg or more .

The activity of lipases in the compositions or oral dosage forms of the present invention can be approximately 4500-25000 IU, for example, approximately 4500-5500 IU, approximately 9000-11000 IU, approximately 13500-16500 IU and approximately 18000-22000 IU. The amylase activity in the compositions or oral dosage forms of the present invention can be approximately 8100-180000 IU, for example, approximately 8000-45000 IU, approximately 17000-90000 IU, approximately 26000-135000 IU, approximately 35000-180000 IU. The activity of proteases in the compositions or oral dosage forms of the present invention can be approximately 8000-134000 IU, for example, approximately 8000-34000 IU, 17000-67000 IU, 26000-100000 IU, 35000-134000 IU. In one embodiment, the lipase activity is in the range of about 4500-5500 IU, the amylase activity is about 8000-45000 IU, and the protease activity is about 8000-34000 IU. In another embodiment, the lipase activity is in the range of about 9000-11000 IU, the amylase activity is about 17000-90000 IU, and the protease activity is about 17000-67000 IU. In yet another embodiment, the lipase activity is in the range of about 13500-16500 IU, the amylase activity is in the range of about 26000-135000 IU and the protease activity is in the range of about 26000-100000 IU. In yet another embodiment, the lipase activity is in the range of about 18000-22000 IU, the amylase activity is about 35000-180000 IU, and the protease activity is about 35000-134000 IU.

The lipase: protease: amylase ratio in the compositions or oral dosage forms of the present invention can range from about 1:10:10 to about 10: 1: 1 or about 1.0: 1.0: 0.15 (by enzyme activity ) The amylase / lipase ratio in the compositions or oral dosage forms of the present invention may be about 1.8-8.2, for example, about 1.9-8.2, or about 2.0-8.2. The protease / lipase ratio in the compositions or oral dosage forms of the present invention may be in the range of about 1.8-6.2, for example, about 1.9-6.1, or about 2.0-6.1.

In another embodiment, the activity of lipase, protease and amylase may correspond to that shown in table A below):

Table a Structure one 2 3 four Activity, ME min Max min Max min Max min Max Lipase 4500 5500 9000 11000 13500 16500 18000 22000 Amylase 8100 45000 17100 90,000 26100 135000 35100 180,000 Protease 8100 34000 17100 67000 26100 100,000 35100 134000 Ratio min Max min Max min Max min Max Amylase / Lipase 1.8 8.2 1.9 8.2 1.9 8.2 2.0 8.2 Protease / lipase 1.8 6.2 1.9 6.1 1.9 6.1 2.0 6.1

The total amount of digestive enzymes (by weight) in the compositions or oral dosage forms of the present invention can be approximately 20-100%, 20-90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30% or approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90% or approximately 100%. In one embodiment, the total amount of digestive enzymes is 60-90%. In another embodiment, the total amount of digestive enzymes (e.g., pancrelipase) is approximately 68-72%.

In one embodiment, in the compositions or oral dosage forms of the present invention containing at least one digestive enzyme, the moisture content is about 3% or less, about 2.5% or less, about 2% or less, about 1.5%, or less than or approximately 1% or less, including all ranges and sub-ranges falling within this framework (i.e., any of about 2.5-3%, 2-3%, 1.5-3%, 1-3%, 2- 2.5%, 1.5-2.5%, 1-2.5%, 1.5-2%, 1-2%, 1-1.5% and so on). It has been found that while maintaining low moisture content, the compositions or oral dosage forms of the present invention are substantially more stable than conventional compositions with a higher moisture content, for example, greater than about 3% or higher.

The term “moisture content”, also called “water content”, means the amount of water that the composition contains. For compositions that do not change volume when the moisture content changes, the moisture content can be expressed volumetrically (i.e., by volume) as the ratio of the mass of moisture to the volume of dry matter. For compositions that change volume when the moisture content changes, the moisture content can be expressed gravimetrically (that is, by weight) as the mass of water removed after drying, per unit dry weight of the sample. Determination of moisture content can be made by any conventional method known in the art. For example, moisture content can be determined by chemical titration, such as Karl Fischer titration, in which a sample is dissolved in an electrochemical titration cell. Water from the sample is consumed during the electrochemical reaction, the end of which is determined potentiometrically, thus, the amount of water in the sample is measured directly. Alternatively, relatively simple thermogravimetric methods, such as “drying loss” (LoD), in which the mass of a sample is measured before and after controlled drying, can be used. Loss of mass after drying is considered a loss of moisture. Commercially available moisture analyzers (e.g. available from Mettler Toledo, Sartorius AG and so on) can also be used to determine moisture content. The moisture content of the compositions or oral dosage forms of the present invention can be measured by any suitable method known in the art, for example, “loss by drying”.

In another embodiment, in the compositions or oral dosage forms of the present invention containing at least one digestive enzyme, the water activity is about 0.6 or less, about 0.5 or less, about 0.4 or less, about 0.3 or less, about 0.2 or less, or about 0.1 or less, including all ranges and subranges that fall within this framework (i.e., any of about 0.5-0.6, 0.4-0.6, 0 , 3-0.6, 0.2-0.6, 0.1-0.6, 0.4-0.5, 0.3-0.5, 0.2-0.5, 0.1 -0.5, 0.3-0.4, 0.2-0.4, 0.1-0.4, 0.2-0.3, 0.1-0.3, 0.1-0 , 2 etc.). It has been found that while maintaining low water activity, the compositions or oral dosage forms of the present invention are substantially more stable than conventional digestive enzyme compositions with higher water activity.

Water activity ("aw") is the relative availability of water in a substance. As used herein, the term “water activity” is defined as the vapor pressure of water from a sample divided by the vapor pressure of pure water at the same temperature. In pure distilled water, the water activity is exactly equal to unity. Water activity depends on temperature. Thus, the activity of water changes as the temperature changes. In the present invention, water activity is measured at a temperature of from about 0 ° C to about 50 ° C, preferably from about 10 ° C to about 40 ° C.

The water activity of the product can be determined by measuring the relative humidity of the air surrounding the sample in equilibrium. Accordingly, the measurement of water activity in a sample is usually carried out in a closed (usually isolated) space where such equilibrium can take place. In equilibrium, the water activity of the sample and the relative humidity are equal, and therefore the measurement of the equilibrium relative humidity in the chamber serves as a measure of the activity of the sample water. At least two different types of water activity meters are commercially available. One type of water activity meter uses the dew point technology of a cooled mirror (for example, AquaLab ™ water activity meters supplied by Decagon Devices, Inc), while the other uses relative humidity or capacitance sensors to measure relative humidity (e.g. , water activity meters from Rotronic). The water activity of the compositions or oral dosage forms of the present invention can be measured by any suitable method known in the art.

In another embodiment, after 6 months of accelerated stability testing in the compositions or oral dosage forms of the present invention containing at least one stabilized digestive enzyme, the loss of enzyme activity is not more than about 25%, not more than about 20%, not more than about 15% , not more than about 12%, not more than about 10%, not more than about 8%, or not more than about 5%.

The term “accelerated stability testing” or “accelerated storage testing” refers to test methods used to model the effect of relatively long storage conditions on enzyme activity; these methods can be performed in a relatively short time. As is known in the art, accelerated stability testing methods are a reliable alternative to real-time stability testing and can accurately predict the shelf life of biological products. Such “accelerated stability testing” conditions are known in the art and are in accordance with the International Conference for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use: Stability Testing of New Drug Substances and Products Q1A - these materials are fully incorporated herein by reference.

One method of accelerated stability testing involves storing samples of the digestive enzyme composition in an airtight bag of Nialene (nylon, aluminum, laminated polyethylene; GOGLIO SpA, Milan) at 40 ° C / 75% relative humidity for 6 months.

After storage (or periodically during storage), the enzyme activity of the samples can be verified using conventional digestive enzyme activity analysis methods (e.g., United States Pharmacopoeia, Pancrelipase: Assay for lipase activity; incorporated herein by reference in its entirety).

Compositions or oral dosage forms of the present invention may also optionally contain one or more stabilizers that increase or improve the stability of the compositions or oral dosage forms of the present invention. Non-limiting examples of suitable stabilizers include proline, trehalose, dextran, maltose, sucrose, mannitol, polyols, silica gel, aminoguanidine, pyridoxamine, anhydrous metal salts such as sodium bicarbonate, magnesium oxide, calcium oxide, alumina, and mixtures thereof. The moisture content of one stabilizer or more may be approximately 3% or less and / or the activity of water is 0.6 or less.

Non-limiting examples of suitable forms of trehalose that can be used in the compositions or oral dosage forms of the present invention include trehalose dihydrate (TD), amorphous trehalose (AT), anhydrous trehalose (eg, anhydrous amorphous trehalose [BAT], anhydrous crystalline trehalose [BKT] ) Powdered anhydrous trehalose may contain BAP and / or BKT. As used herein, the term “trehalose” refers to any physical form of trehalose, including anhydrous, partially hydrated, fully hydrated, as well as mixtures and solutions thereof. The term “anhydrous trehalose” refers to any physical form of trehalose containing less than 2% water. Anhydrous forms of trehalose may contain 0-2% water. Amorphous trehalose contains approximately 2-9% water, and trehalose dihydrate contains approximately 9-10% water. Anhydrous trehalose can be prepared as described in PCT / GB97 / 00367, which is incorporated herein by reference in its entirety. In one embodiment, the compositions or oral dosage forms of the present invention comprise one or more stabilized digestive enzymes and anhydrous trehalose.

The amount of anhydrous trehalose (BAT or BKT) in the composition of the present invention can be in the range of about 5-50%, 5-40%, 5-30%, 5-20%, 5-15%, 5-10%, 7- 15%, or approximately 5%, approximately 7%, approximately 10%, approximately 15%, or approximately 20%.

Anhydrous trehalose may be included in the composition or oral dosage form of the present invention in powder form. The particle size of the anhydrous trehalose powder may be in the range of about 2-2000 microns.

Compositions or oral dosage forms of the present invention contain one stabilized digestive enzyme or more and anhydrous trehalose, giving the enzymes improved stability. Anhydrous trehalose is believed to stabilize the compositions or oral dosage forms of the present invention by absorbing or binding moisture from the environment or residual moisture left over from production or within the composition.

Depending on the intended purpose and requirements for the compositions, the ratio by weight of the stabilized digestive enzyme to the stabilizer is in the range from about 99: 1 to 80:20. The stabilizer may be included in the compositions or oral dosage forms of the present invention by wet or dry mixing of at least one stabilized digestive enzyme with at least one stabilizer. In one embodiment, one stabilized digestive enzyme or more in dry form is mixed with one stabilizer or more. In another embodiment, one stabilized digestive enzyme or more in wet form is mixed with one stabilizer or more.

In addition to the stabilized digestive enzyme and / or stabilizer (s), the compositions or oral dosage forms of the present invention may further comprise one or more pharmaceutically acceptable excipients. The term “excipients” includes other pharmaceutically acceptable ingredients added to the active component (s) of the composition (eg, stabilized digestive enzymes) to improve processing, stability, palatability and so on. Non-limiting examples of suitable excipients include pharmaceutically acceptable binders, stabilizers, disintegrants, lubricants, glidants, diluents and mixtures thereof, and so on. It will be clear to those skilled in the art of pharmaceutical formulations that a particular excipient may fulfill numerous functions in a composition. So, for example, the binder can also function as a diluent and so on. The moisture content of the fillers may be about 3% or less, and / or their water activity is about 0.6 or less.

Non-limiting examples of suitable binders include starches, sugars (e.g. lactose), sugar alcohols (e.g. xylitol, sorbitol, maltitol), cellulose (e.g. microcrystalline cellulose), modified cellulose (e.g. hydroxypropyl cellulose, sodium carboxymethyl cellulose), alginic acid hydrochloride, ) and mixtures thereof. Non-limiting examples of suitable disintegrants include dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, alginic acid, hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cellulose, cellulose, cellulose, cellulose, alum, cross-linked polyvinylpyrrolidone), microcrystalline cellulose, sodium carboxymethyl starch, g sodium starch lycolate, starches (corn starch, rice starch) and mixtures thereof. Non-limiting examples of suitable lubricants include calcium stearate, magnesium stearate, sodium stearyl fumarate, stearic acid, zinc stearate, talc, waxes, Sterotex ^® , Stearowet ^® and mixtures thereof. Non-limiting examples of suitable glidants include colloidal silicon dioxide, talc and mixtures thereof. Non-limiting examples of suitable diluents include mannitol, sucrose, anhydrous dibasic calcium phosphate, anhydrous dibasic calcium phosphate, tribasic calcium phosphate, cellulose, lactose, magnesium carbonate, microcrystalline cellulose, and mixtures thereof. Non-limiting examples of suitable stabilizers include trehalose, proline, dextran, maltose, sucrose, mannitol, polyols, silica gel, aminoguanidine, pyridoxamine, and mixtures thereof.

In one embodiment, the disintegrant is crospovidone (e.g., POLYPLASDONE XL, POLYPLASDONE XL-10). In another embodiment, the disintegrant is croscarmellose sodium (e.g., AC-DI-SOL). In another embodiment, the disintegrant is sodium starch glycolate (e.g., EXPLOTAB, EXPLOTAB CV). In another embodiment, the compositions or oral dosage forms of the present invention may comprise a combination of disintegrants, for example, microcrystalline cellulose and sodium starch glycolate or croscarmellose sodium and crospovidone.

The amount of baking powder can be in any range of approximately 0.1-30%, 1-30%, 1-25%, 1-20%, 1-15%, 1-10%, 1-5%, 5-10 %, 5-15%, 5-20%, 5-25% or 5-30%. In one embodiment, the amount of disintegrant is about 2-4%, or about 2-3%, or about 2.5%.

Non-limiting examples of suitable diluents include microcrystalline cellulose, starch, calcium phosphate, lactose, sucrose, mannitol, sorbitol, and combinations thereof. In one embodiment, the diluent is microcrystalline cellulose (e.g., Avicel). In another embodiment, the diluent is starch. In another embodiment, the diluent is lactose (e.g., Pharmatol). In another embodiment, the compositions or oral dosage forms of the present invention may contain a combination of diluents, such as microcrystalline cellulose, starch and lactose.

The amount of diluent can be in any range of approximately 0.1-99%, 1-30%, 1-25%, 1-20%, 1-15%, 1-10%, 1-5%, 5-10 %, 5-15%, 5-20%, 5-25% or 5-30%. In one embodiment, the amount of diluent is about 2-5%, 3-5%, or about 4%.

One or more excipients of the compositions or oral dosage forms of the present invention may function as a moisture absorber to further stabilize the composition. Suitable excipients suitable as desiccants include any pharmaceutically acceptable excipient that strongly binds water or reduces the water activity of the composition. For example, the composition of the present invention may contain about 1-4% silica gel or about 2.5% silica gel.

The compositions of the present invention can be obtained in the form of any suitable oral dosage form. Non-limiting examples of suitable dosage forms include tablets, capsules, and sachets. Since certain digestive enzymes, such as pancreatic lipases, must be protected against inactivation in the stomach prior to release in the duodenum, it may be desirable for the stabilized digestive enzyme compositions or oral dosage forms of the present invention to be formulated as controlled or delayed release formulations. Such controlled or delayed release formulations may include enteric-coated tablets or particles that serve to protect pH-sensitive digestive enzymes from inactivation in the stomach to the release of digestive enzymes in the duodenum. Alternatively, controlled release formulations may include capsules filled with stabilized digestive enzyme compositions or oral dosage forms of the present invention, where the capsule protects the contents from inactivation in the stomach, while releasing digestive enzymes into the duodenum. However, the stabilized digestive enzyme compositions or oral dosage forms of the present invention are not limited to digestive enzymes susceptible to inactivation in the stomach, and, for example, may include certain digestive enzymes that are naturally stable in the gastric environment, such as gastric lipases, a number of proteases, including those pancreatic origin, and amylase. Certain digestive enzymes obtained or extracted from microorganisms are stable or chemically modified by crosslinking.

If tablets are formed from the compositions of the present invention, the stabilized digestive enzyme (s) may (gut) be “tabletted (s)” (i.e., converted (s) into tablets) using methods known in the art and then enteric coated coated, again using methods known in the art.

If capsules are formed from the compositions of the present invention, the contents of the capsule can be obtained using methods known in the art. For example, a stabilized digestive enzyme composition can be prepared in the form of particles or tablets suitable for incorporation into a capsule.

The term "particles", as used herein, includes substances in the form of fine powders (with particle diameters in the range of about 1 μm) to pellets having a diameter of about 5 mm.

Coated particles can also be prepared from the stabilized digestive enzyme composition, wherein the coating contains an enteric polymer. The term “enteric polymer” means a polymer that protects digestive enzymes from the contents of the stomach, for example, a polymer that is stable at acidic pH but can degrade quickly at a higher pH, or a polymer whose hydration or erosion rate is slow enough to ensure that the contact of the contents of the stomach with digestive enzymes will be relatively insignificant while they are in the stomach, in contrast to the rest of the gastrointestinal tract. Non-limiting examples of enteric soluble polymers include those known in the art, such as modified or unmodified natural polymers, for example cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate and shellac; or synthetic polymers, for example acrylic polymers or copolymers, or methacrylic acid polymers and copolymers, methyl methacrylate copolymers and methacrylic acid / methyl methacrylate copolymers.

The enteric polymer coating may be a synthetic polymer, optionally including an inorganic substance, such as an alkalizing agent. The resulting coated particles are pellets containing a core comprising stabilized digestive enzyme (s) and an enteric coating encapsulating the core. From particles of a stabilized digestive enzyme coated with tablets, tablets or capsules can be prepared.

An enteric polymer and at least one inorganic substance impart enteric properties to the coating of the present invention. Thus, when used as a drug, the coating will act as a barrier, protecting the drug from the acidic environment of the stomach, and essentially prevent the release of the drug before it reaches the small intestine (i.e., the release of the enzyme in the stomach will be less than about 10-20% of the total the amount of enzyme in the composition).

The inorganic substance may include, for example, an alkalizing agent. Non-limiting examples of alkalizing agents include silica, sodium salts, calcium salts, magnesium salts, aluminum salts, aluminum hydroxides, calcium hydroxides, magnesium hydroxides, talc, and combinations thereof. In one embodiment, the alkalizing agent is talc.

Depending on the intended purpose of the composition, the ratio of enteric polymer to at least one inorganic substance may range from about 10: 1 to about 1:60 by weight. In another embodiment, the ratio of the enteric polymer to the at least one inorganic substance ranges from about 8: 1 to about 1:50 by weight. In another embodiment, the ratio of the enteric polymer to the at least one inorganic substance ranges from about 6: 1 to about 1:40 by weight. In another embodiment, the ratio of the enteric polymer to the at least one inorganic substance ranges from about 5: 1 to about 1:30 by weight. In another embodiment, the ratio of enteric polymer to at least one inorganic substance ranges from about 4: 1 to about 1:25 by weight. In another embodiment, the ratio of the enteric polymer to the at least one inorganic substance ranges from about 4: 1 to about 1: 9 by weight. In another embodiment, the ratio of the enteric polymer to the at least one inorganic substance ranges from about 10: 4 to about 10: 7 by weight.

In one embodiment, the compositions or oral dosage forms of the present invention comprise stabilized digestive enzyme particles coated with an enteric coating that contains an enteric polymer and an inorganic substance, such as talc. In a specific embodiment, the inorganic substance of the enteric coating comprises about 1-10 wt.% Of the total particle weight. In another embodiment, the inorganic substance contains about 3, about 5, about 7, or about 10 wt.% Particles. In other embodiments, the inorganic substance is an alkalizing agent and comprises about 20-60% of the dry weight of the coating. In other embodiments, the alkalizing agent comprises approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, or approximately 55% of the dry weight of the coating (including all ranges, subranges, and values falling within these ranges) ) In a specific embodiment, the alkalizing agent is talc. In another specific embodiment, the dry coating of particles contains approximately 35% talc.

In another embodiment of the present invention, the coating further comprises a plasticizer. Examples of suitable plasticizers include, but are not limited to, triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacinate, polyethylene glycol, polypropylene glycol, castor oil, acetylated monoglyceride, acetylated digly thereof.

Dosage forms of the present invention can be capsules containing the composition of the present invention (for example, particles with controlled release of the composition of stabilized digestive enzymes coated with an enteric polymer and alkalizing agent). The capsules themselves may consist of any conventional biodegradable substance known in the art, for example gelatin, polysaccharides such as pullulan, or modified cellulosic materials, for example hydroxypropyl methylcellulose. To improve the stability of stabilized digestive enzymes, the capsule may be dried to fill or a capsule consisting of a low moisture content material may be selected. In one embodiment of the dosage form of the present invention, the capsule consists of hydroxypropyl methylcellulose. In another embodiment of the dosage form of the present invention, the capsule consists of hydroxypropyl methylcellulose having a water content of about 6% or less, for example, any water content of about 4% or less, 2% or less, or 2-6%, or 4-6 % In another embodiment, the capsule consists of hydroxypropyl methylcellulose having a water content of less than about 2%.

Dosage forms of the present invention may contain a single digestive enzyme or a mixture of digestive enzymes. If a stabilized digestive enzyme composition is formulated as an enteric coated particles, each coated particle may contain a core containing one digestive enzyme or a mixture of digestive enzymes. The dosage form may also contain particles having a coating, each of which has nominally the same composition, or the dosage form may contain mixtures of various types of particles with a coating. For example, the dosage form may be a capsule filled with coated particles, where each of the coated particles has a core containing pancrelipase. Alternatively, the dosage form may be a capsule filled with coated particles, where some of the coated particles have a core containing pancrelipase, while other coated particles have nuclei containing another lipase or protease or amylase. In order to provide the desired therapeutic effect, any suitable combination of coated particles consisting of various compositions may be used.

In addition, if the dosage forms of the present invention consist of coated particles of stabilized digestive enzymes, each individual particle may have the same coating composition or may contain mixtures of particles, some of which have a different coating composition. Any suitable combination of coating compositions may be used to provide the desired type of controlled release or therapeutic effect.

The coated particle cores may be of any suitable particle size or shape. For example, the coated particles may be in the form of a powder with a particle size range of about 50-5000 microns, or may be in the form of "mini-tablets" with a nominal particle diameter in the range of about 2-5 mm. For other applications, coated particle cores may be “microtablets” in which the nominal particle diameter is less than about 2 mm, for example, about 1-2 mm.

In one embodiment, the compositions or oral dosage forms of the present invention may comprise a plurality of coated digestive enzyme particles (e.g., pancrelipase). Particles of digestive enzymes may contain a digestive enzyme, at least one disintegrant, at least one polymer binder or diluent, and optionally at least one plasticizer, optionally at least one glidant and optionally at least one lubricant. In one embodiment, the digestive enzyme particles may contain about 60-90% of the digestive enzyme, about 1-4% of at least one disintegrant, about 2-6% of at least one polymeric binder or diluent, and optionally about 0.5-1, 0% of at least one plasticizer, optionally about 0.2-0.6% of at least one glidant, and optionally about 0.2-0.6% of at least one lubricant. For example, digestive enzyme particles may contain approximately 60-90% pancrelipase, approximately 1-4% croscarmellose sodium, approximately 0.5-1.0% hydrogenated castor oil, approximately 0.2-0.6% colloidal silicon dioxide, approximately 2 -6% microcrystalline cellulose and approximately 0.2-0.6% magnesium stearate. The coating may contain at least one enteric polymer, about 4-10% of at least one alkalizing agent (based on the total particle weight) and optionally at least one plasticizer. In one embodiment, the coating may contain about 10-20% of at least one enteric polymer, about 4-10% of at least one alkalizing agent, and about 1-2% of at least one plasticizer (based on total particle weight). For example, a coating may contain about 10-20% hydroxypropyl methylcellulose phthalate, about 4-10% talc and about 1-2% triethyl citrate (based on total particle weight). Then, from a plurality of coated particles of digestive enzymes, a tablet may be formed, or a capsule filled with these particles. In one embodiment, the capsule comprises hydroxypropyl methyl cellulose.

The compositions of the present invention and dosage forms containing the compositions of the present invention have improved stability compared to conventional compositions and dosage forms of digestive enzymes (e.g., pancrelipase). Therefore, the dosage forms of the present invention do not require “overfilling” (ie, are “zero overfilling”) - introducing an excess of the active substance, like conventional dosage forms of digestive enzymes, in order to deliver a clinically applicable amount of the digestive enzyme to a patient in need thereof . Conventional digestive enzyme compositions and dosage forms require an excess of active ingredient as high as 65% (i.e., contain 165% of the required dose of the digestive enzyme) to compensate for the low stability of the enzymes. As a result, uncertainty about the dose delivered by conventional digestive enzyme compositions is created. Thus, conventional “overfilled” dosage forms soon after their manufacture may deliver higher than expected doses of digestive enzymes, but over time, enzymatic activity may fall below the expected dose.

In one embodiment, dosage forms containing the compositions of the present invention are essentially “zero overflow” forms. The term “substantially zero overflow” means compositions of the present invention in which the level of additional digestive enzymatic activity (i.e., the amount of additional enzymatic activity in excess of the intended dose) is less than or equal to about 10%, that is, about 10%, less than about 10 %, less than or equal to about 9%, less than or equal to about 8%, less than or equal to about 7%, less than or equal to about 6%, less than or equal to about 5%, less than or equal but about 4%, less than or equal to about 3%, less than or equal to about 2%, less than or equal to about 1% or about 0%. So, for example, if the estimated dose is approximately 4,500 IU of lipase, the substantially "unfilled" compositions of the present invention may contain less than or equal to approximately 4,950 IU of lipase (i.e., less than or equal to 110% 4,500 IU of lipase). In another embodiment, the “unfilled” dosage form contains 4,500 IU of lipase.

The compositions or dosage forms (e.g., tablets or capsules) of the present invention may be stored in any suitable packaging. For example, the package may be a glass or plastic vessel with a threaded or dense cork. Alternatively, the compositions or dosage forms of the present invention may be packaged in unit dosage form in “blister packs”. Applicants have found that enhanced stability of the compositions or dosage forms of digestive enzymes can be achieved by using a moisture-proof insulating layer and / or moisture-proof packaging. Non-limiting examples of suitable moisture-proof packaging include glass bottles, plastic bottles containing waterproofing resins or coatings, aluminized plastic packaging (e.g., Mylar), and so on. The term "moisture-proof" refers to a package in which the permeability to water is less than 0.5 mg of water per cubic centimeter of container volume per year.

Containers (e.g. bottles) can be closed with any suitable lid, especially lids, which minimize the ingress of moisture during storage. For example, the compositions or dosage forms of the present invention can be closed with caps such as Saf-Cap III-A (Van Blarcom Closures, Inc.), which contains HS 035 Heat Seal / 20F (SANCAP Liner Technology, Inc.) as a sealant gaskets.

To ensure the integrity of the package and minimize the penetration of moisture during storage, sealed packages containing the composition or dosage form of the present invention can be tested for leaks after filling the composition or dosage form of the present invention and sealing the package. For example, sealed packages can be checked by applying a controlled vacuum to the lid and detecting a decrease in vacuum over time. Suitable leak testing equipment includes those manufactured by Bonfiglioli (e.g. model LF-01-PKV or model PKV 516).

Packages containing the compositions or dosage forms of the present invention may also contain a desiccant (i.e., a substance that absorbs or absorbs water or reacts with it) capable of reducing moisture inside the package, for example, a capsule of a desiccant capable of removing moisture from an atmosphere sealed inside packaging. Non-limiting examples of suitable moisture absorbers that can be placed in such packages include zeolites (e.g., molecular sieves, e.g., 4Å molecular sieves), clay (e.g., montmorillonite), silica gel, activated carbon, or combinations thereof. In one embodiment, the desiccant comprises molecular sieves.

In addition, it is common practice to add a “plug” of cellulosic polymer, such as cotton wool, to the top of the container when packing oral pharmaceutical doses, to fill the empty space at the top of the container, thereby minimizing the movement of contents. Cellulosic polymers are somewhat hygroscopic and can act as a “reservoir” of moisture in the package. Accordingly, in one embodiment of the packaging of the present invention, there is no “plug” of cellulosic polymer or cotton in the packaging. In another embodiment of the packaging of the present invention, the packaging is free from a “plug” of cellulosic polymer or cotton wool and contains a desiccant.

The compositions of the present invention can be prepared using conventional methods, but modified as described herein to provide a moisture content of about 3% or less, water activity of about 0.6 or less, or to obtain stabilized digestive enzyme compositions that lose no more activity. than about 15% after 3 months of accelerated stability testing. For example, particles of digestive enzymes (e.g. pancrelipase) may be coated in a fluidized bed apparatus, where the apparatus is equipped with a desiccant. In one embodiment, the coating apparatus operates in an atmosphere with a water content of about 4 g / m ³ or less, about 3.5 g / m ³ or less, about 3 g / m ³ or less, about 2.5 g / m ³ or less, about 2.0 g / m ³ or less, about 1.5 g / m ³ or less, about 1.0 g / m ³ or less, or about 0.5 g / m ³ or less, including all ranges and subranges that fall within the given frame. The atmosphere in which the coating is applied may contain dehydrated air, dehydrated nitrogen or other dehydrated inert gas.

The coating may be applied as a solution of an enteric polymer (and optionally suspended inorganic substance) in an organic solvent such as alcohol (e.g. ethanol), ketone (e.g. acetone), methylene chloride, or mixtures thereof (e.g., a mixture of ethanol and acetone).

The compositions of the present invention provide improved absorption of fats, proteins and carbohydrates in patients suffering from conditions or disorders associated with a lack of digestive enzymes. In one embodiment, the compositions of the invention, namely, pancrelipase or pancreatin compositions, can be used to treat exocrine pancreatic insufficiency (ESF) associated with various diseases. Such diseases include, but are not limited to, cystic fibrosis. In some embodiments, the implementation of such compositions can essentially facilitate malabsorption (eg, fat) associated with ESR in patients with cystic fibrosis and other patients, including pediatric patients. In some embodiments, the implementation of such compositions can increase in patients with cystic fibrosis the absorption coefficient of fats to at least about 85% or more. Such results can be obtained by simultaneous administration with other agents or compositions, or can be obtained without co-administration with other agents. In one embodiment, such fat absorption coefficients are achieved without co-administration of proton pump inhibitors such as Prilosec ^®, Nexium ^®, etc.

In patients diagnosed with low gastrointestinal pH (e.g., gastrointestinal pH less than about 4), improved results can be obtained by administering the compositions or dosage forms of the present invention along with proton pump inhibitors, antacids, and other drugs that increase gastrointestinal pH . For example, the compositions or dosage forms of the present invention can be administered separately from proton pump inhibitors, antacids, or other drugs (before, at the same time, or after administration of a proton pump inhibitor, antacids, and so on). Alternatively, a proton pump inhibitor, antacid, or other drug may be combined with the pancreatin composition of the present invention in a single dosage form.

Another embodiment of the present invention relates to a method for treating or preventing a digestive enzyme deficiency disorder comprising administering a composition of the present invention to a mammal in need thereof. In one embodiment, the mammal is a human.

Another embodiment of the present invention relates to a method for treating or preventing a digestive enzyme deficiency disorder comprising administering a composition or dosage form of the present invention to a mammal in need thereof, wherein the composition or dosage form of the present invention contains, in addition to at least one digestive enzyme, proton pump inhibitor, antacid or other drug that increases the pH of the gastrointestinal tract. Another embodiment of the present invention relates to a method for treating or preventing a digestive enzyme deficiency disorder comprising administering a composition or dosage form of the present invention in combination with a dosage form containing a proton pump inhibitor, antacid or other drug that increases the pH of the gastrointestinal tract.

Disorders that can be treated with the composition or dosage form of the present invention include conditions in which the patient has no digestive enzymes or is very small, or in which patients need additional administration of digestive enzymes. For example, such conditions may include cystic fibrosis, chronic pancreatitis, other pancreatic diseases (e.g., hereditary, post-traumatic pancreatitis and allograft pancreatitis, hemochromatosis, Schwachmann syndrome, lipomatosis or hyperparathyroidism), side effects of cancer or its treatment, side effects of surgery (e.g., shun surgery Gastrointestinal tract, Whipple procedures, total pancreatectomy and so on) or other conditions in which pancreatic enzymes cannot reach the intestine, poor mixing (for example, gast Billroth II ectomy, other types of gastrointestinal bypass surgery, gastrinoma, and so on), side effects of pharmacotherapy, such as treatment with metformin or drugs to treat HIV symptoms and autoimmune diseases, such as diabetes, in which pancreatic function may be at risk, obstruction (for example, lithiasis of the bile duct and pancreatic duct, pancreatic and duodenal tumors, duct stenosis), malabsorption associated with celiac disease, food allergies and aging.

The amount of a composition or dosage form of the present invention administered to a mammal (eg, humans) per day depends on the expected result. A qualified doctor will be able to prescribe the necessary dose based on the diagnosis of the condition that will be treated.

For example, to treat digestive enzyme deficiency in humans (for example, with cystic fibrosis), the starting dose should be 500-1000 units of lipase / kg / meal, and the total dose should not exceed 2500 units of lipase / kg / meal or 4000 units of lipase / grams of fat / meal as recommended by the US FDA. Typically, the patient should receive at least 4 dosage forms per day, preferably with food.

EXAMPLES

Example 1

Pancrelipase MT (mini-tablets) are a mixture of pancrelipase feed (eg, obtained from Nordmark) and excipients, tabletted using round beveled punches with a diameter of 2 mm. Physical features of MT pancrelipase before coating are shown below in table 1.

Table 1 Diameter 2.0 mm Mass (10 MT) 0.074-0.086 g Thickness (average value for 10 MT) 2.2 ± 0.2 mm Hardness 0.5-2.0 Kp Fragility * (20 g MT, 30 minutes at 25 rpm) 0.0-2.5% * USP

The coating composition was applied to MT pancrelipase (Table 2) using a Glatt-GPCG1 fluidized bed apparatus equipped with a Munters ML 1350 dehumidifier for the air flow involved in the process. The coating process was performed at three different values of the moisture content of the air flow involved in the process (table 3). For each batch, the coating weight was approximately 15% of the total weight of the coated particles. The composition of the coated particles for each set of process conditions was approximately the same (Table 4), and the coating looked uniform, smooth, and homogeneous after microscopic examination.

table 2 Substance % (wt./wt.) Hypromellose Phthalate (HP55) 10.19 Triethyl citrate 1,02 Talc 1,02 Ethanol 96% 79.78 Acetone 7.99 100.00

Table 3 The consignment The moisture content of the air involved in the process, g / m ³ P9A165 8.8 P9A167 0.4 P9A170 3.6

Table 4 Substance Coating composition,% (wt./wt.) MT Pancrelipase 85.00 Hypromellose Phthalate (HP55) 12.50 Triethyl citrate 1.25 Talc 1.25 100.00

In three sets of samples (i.e., P9A165, P9A167, and P9A170), the residual moisture content corresponded to the moisture content of the air stream involved in the process (Table 4).

Table 5 The consignment Loss on drying,% P9A165 2,8 P9A167 1,1 P9A170 1.7

The effect of residual moisture on activity loss over time was evaluated under accelerated stability testing as follows.

Hard gelatin capsules (20,000 IU lipase dose) were filled with three batches of coated MT pancrelipase described above and stored at 40 ° C and 75% relative humidity in sealed Nialene bags.

Lipase activity was evaluated after 15 days and after 4 months of storage. The results are shown in table 6.

Table 6 Reference point 15 days 4 months The consignment Loss on drying Lipase, IU / mg P9A165 (2.8%) 62.5 46 (activity -26%) 33.6 (activity -46%) P9A167 (1.1%) 64.5 53 (activity -18%) 46.2 (activity -28%) P9A170 (1.7%) 63.8 53 (activity -17%) 44.8 (activity -30%)

From the results of table 6 it follows that improved stability is characteristic of compositions having a moisture content of less than about 2%. Alternatively, improved stability is achieved by coating in an atmosphere with a moisture content of less than 3.6-0.4 g / m ³ .

Example 2

Two pan coating compositions containing varying amounts of talc were applied to MT pancrelipases (Table 7).

Table 7 Composition,% (wt./mass.) Substance Low talc content High talc content Hypromellose Phthalate (HP55) 10,190 5,825 Triethyl Citrate (CHP) 1,020 0.580 Talc 1,020 5,825 Ethanol 96% 79,780 79,780 Acetone 7,990 7,990 100,000 100,000 HP: TPP: talc ratio 10: 1: 1 10: 1: 10 Total solids 12.23% 12.23%

Coating tests were performed using a Glatt-GPCG1 fluidized bed apparatus equipped with a Munters ML 1350 dehumidifier to ensure the process was carried out at low air humidity (i.e. below 1 g / m ³ ). The coating weight was approximately 15%. The theoretical composition of these two batches is shown in table 8. Microscopic examination showed that the coating on all samples was smooth and homogeneous. The residual moisture content was measured by loss during drying (table 9).

Table 8 The consignment P9A230 P9A240 Substance Low talc content High talc content Composition,% (wt./wt.) MT Pancrelipase 85,000 85,000 Hypromellose Phthalate (HP55) 12,500 7,143 Triethyl citrate 1,250 0.714 Talc 1,250 7,143 100,000 100,000

Table 9 The consignment Loss on drying,% P9A230 0.9 P9A240 0.9

The effect of various coating compositions on the loss of activity over time was evaluated under conditions of accelerated stability testing as follows.

Hard gelatin capsules (20,000 IU lipase dose) were filled with two batches of coated MT pancrelipase as described above and stored at 40 ° C and 75% relative humidity in sealed Nialene bags.

Lipase activity was checked after 1, 2 and 3 months of storage, as shown in table 10.

Table 10 Time reference 1 month 2 months 3 months The consignment Lipase (IU / mg) P9A230 Low talc content 64.5 57.6 (activity -11%) 49.6 (activity -23%) 52.3 (activity -19%) P9A240 High talc content 65.3 58.2 (activity -11%) 60.62 (activity -7%) 59.6 (activity -9%)

The results showed that the loss of activity after three months of storage under conditions of accelerated stability testing is significantly lower for samples whose coating has a high talc content (lot P9A240). Accordingly, an increase in talc concentration from about 1% to about 7% leads to statistically significant improvements in enzyme stability.

Example 3

The effect of the coating solvent of the composition was evaluated by obtaining coating compositions with a “high talc content” and a “low talc content” similar to those described in Table 7, except that the solvent ethanol (96% ethanol, 4% water) / acetone was replaced with 100 % acetone (table 11).

Table 11 Composition,% (wt./mass.) Substance Low talc content High talc content Hypromellose Phthalate (HP55) 10,190 5,825 Triethyl Citrate (CHP) 1,020 0.580 Talc 1,020 5,825 Acetone 87,770 87,770 100,000 100,000 HP: TPP: talc ratio 10: 1: 1 10: 1: 10 Total solids 12.23% 12.23%

Coating tests were performed using a Glatt-GPCG1 fluidized bed apparatus equipped with a Munters ML 1350 dehumidifier to ensure the process was carried out at low air humidity (i.e. below 1 g / m ³ ). The coating weight was approximately 15%. The theoretical composition of these two parties is given in table 12.

Table 12 The consignment P9A318
Low talc content P9A352
High talc content Substance Composition,% (wt./mass.) MT Pancrelipase 85,000 85,000 Hypromellose Phthalate (HP55) 12,500 7,143 Triethyl citrate 1,250 0.714 Talc 1,250 7,143 100,000 100,000

Lot P9A318 met the specifications for commercial products, and lot P9A352 did not pass the test for stability in the digestive tract. Microscopy showed that the film coating of the P9A352 batch was not as smooth and homogeneous as that of other coated samples, probably due to the higher evaporation rate of acetone compared to the ethanol / acetone mixture used in previous samples and the high concentration of talc in the coating .

The batch of P9A318 was then evaluated under accelerated stability testing as follows.

Hard gelatin capsules (20,000 IU lipase dose) were prepared and stored at 40 ° C and 75% relative humidity in sealed Nialene bags. Lipase activity was measured after 1, 2 and 3 months of storage, as shown in table 13.

Table 13 Time reference 1 month 2 months 3 months The consignment Lipase (IU / mg) P9A318 Low talc content 63.6 59.5 (activity -6%) 60.4 (activity -5%) 55.4 (activity -13%)

The stability of the batch P9A318 has improved significantly compared to the stability of the batch P9A230, which was prepared with a similar coating under similar coating conditions (table 14). Therefore, it seems that replacing 96% ethanol with acetone in the coating composition provides a significantly lower loss of enzyme activity over time.

Table 14 Faster stability testing at 40 ° C + 75% RH 1 month 2 months 3 months The consignment HP: TPP: talc Talc content Solvent Lipase (loss of activity) P9A230 10: 1: 1 Low Ethanol / acetone -eleven% -23% -19% P9A240 10: 1: 10 High Ethanol / acetone -eleven% -7% -9% P9A318 10: 1: 1 Low Acetone -6% -5% -13%

Example 4

Capsules of gelatin and HPMC (hydroxypropyl methylcellulose) were filled with identical coated lipase compositions. The water content in gelatin capsules was approximately 14%, in HPMC capsules approximately 4%. In addition, one set of HPMC capsules was dried to a moisture content of less than 2%. All samples were subjected to accelerated stability testing (40 ° C and 75% relative humidity); samples were sealed in bags from Nialene, and lipase activity was checked after 15, 30 and 90 days. The results are shown below in tables 15-17.

1) Capsules from HPMC against gelatin

Table 15 Party P200450287 The loss of lipase activity,% Time Gelatin capsules HPMC capsules (non-dried) 15 days -12% -3% 30 days -21% -13%

Table 16 Party P200450614 The loss of lipase activity,% Time Gelatin capsules HPMC capsules (dried) 30 days -eleven -one

Table 17 Lot P200450653 The loss of lipase activity,% Time Gelatin capsules HPMC capsules (non-dried) 30 days -fourteen -8 90 days -32 -eighteen

As shown in tables 15-17, lipase compositions in HPMC capsules maintained significantly higher lipase activity after storage for 15, 30, and 90 days with accelerated stability testing, and dried HPMC capsules provide better stability than capsules with an equilibrium moisture level .

Example 5

Capsules of gelatin and hydroxypropyl methylcellulose were filled with mini-tablets from coated lipase compositions. The coating for gelatin capsule compositions (P200050) contained approximately 10% talc, while the coating for hydroxypropyl methylcellulose capsule compositions (P200550) contained approximately 33% talc. In other respects, the coating compositions were identical. The following table 18 compares the levels of decomposition observed after storage under conditions of accelerated stability testing at different moisture content of the compositions. As shown in table 18, higher lipase activity correlates with lower moisture composition. In addition, the compositions with which the HPMC capsules were filled are more stable than the compositions with which the gelatin capsules were filled.

Table 18 GPMC % activity Loss on drying,% Month 40 ° C / 75% rel. humidity Month 40 ° C / 75% rel. humidity The consignment 0 one 3 6 0 one 3 6 P200550 503 one hundred one hundred 105 101 1,6 1.7 1,6 1,5 P200550 865 one hundred 96 101 102 1.7 2.1 1,6 1.8 P200550 500 one hundred 102 101 98 0.8 1.9 1.7 2 P200550 861 one hundred 97 103 99 1,5 1.7 2.0 1.4 P200550 502 one hundred one hundred 99 98 0.4 1.4 2,3 2.0 P200550 859 one hundred 103 103 97 1,1 0.7 1.9 1.3 Average one hundred one hundred 102 99 1,2 1,6 1.9 1.7 Gelatin % activity Loss on drying,% Month 40 ° C / 75% rel. humidity Month 40 ° C / 75% rel. humidity The consignment 0 one 3 6 0 one 3 6 P200050 981 one hundred 90 92 81 2.9 3.0 3.0 2,8 P200050 975 one hundred 89 79 66 2.7 3.2 3,1 2,8 P200050 977 one hundred 96 93 87 3.2 3.4 3.2 2.9 Average one hundred 92.5 86 77 3.0 3.3 3.2 2.9

Example 6

The effect of storing capsules containing lipase compositions in desiccant bags was evaluated by measuring lipase activity in samples after 30 and 90 days of storage under accelerated stability testing (40 ° C and 75% relative humidity; samples were sealed in bags from Nialene) . As shown in tables 19 and 20, lipase activity is significantly higher in bags containing a desiccant, and in capsules dried below the equilibrium moisture content.

2) Dehumidifiers

Desiccant 1: silica gel in Tyvek ^® bags

Desiccant 2: Tyvek ^® molecular sieves

Table 19 The loss of lipase,% Time P200450614 in HPMC capsules (dried) without a desiccant P200450614 in HPMC capsules (dried), desiccant 1 P200450614 in HPMC capsules (dried), desiccant 2 30 days -one + 4 + 1 90 days -10 + 2 0

Table 20 The loss of lipase,% Time P200450653 in HPMC capsules without a desiccant P200450653 in HPMC capsules, desiccant 1 P200450653 in HPMC capsules, desiccant 2 30 days -8 -8 -5 90 days -eighteen -fourteen -10

Example 7

Two coating compositions were applied to MT particles of pancrelipase in which the talc content was between "low" and "high", used above (HP55: CHP: talc = 10: 1: 5), using either acetone or ethanol / acetone. The theoretical composition of the two coating suspensions is shown in table 21 below.

Table 21 Composition,% (wt./wt.) Substance Intermediate Talc Hypromellose Phthalate (HP55) 7,644 7,644 Triethyl Citrate (CHP) 0.764 0.764 Talc 3,822 3,822 Ethanol 79,780 Acetone 7,990 87,770 100,000 100,000 HP: TPP: talc ratio 10: 1: 5 10: 1: 5 Total solids 12.23% 12.23%

Coating tests were performed using a Glatt-GPCG1 fluidized bed apparatus equipped with a Munters ML 1350 dehumidifier to ensure the process was carried out at low air humidity (i.e. below 1 g / m ³ ).

Batch was obtained by coating MT pancrelipase with a coating weight of approximately 15%. Three batches were prepared with ethanol / acetone coating solvent and three batches were prepared with acetone coating solvent. The theoretical composition, which was the same for all six parties, is given below in table 22.

Table 22 The consignment P9A483 - P9A485 - P9A486, solvent - ethanol / acetone P9A405 - P9A476-P9A477 solvent-acetone Substance Composition,% (wt./wt.) MT Pancrelipase 85.00 85.00 Hypromellose Phthalate (HP55) 9.37 9.37 Triethyl citrate 0.94 0.94 Talc 4.69 4.69 100.00 100.00

Microscopy showed that the coating in all six samples was smooth and homogeneous. Pancrelipase coated MT particles were then filled with HPMC capsules, which were packaged in glass bottles containing desiccants (molecular sieves). The bottles were sealed and stored under accelerated stability testing; lipase activity was determined at different time periods, as indicated below in table 23.

The packaging conditions for each sample were as follows: 12 HPMC capsules (20,000 IU lipase dose) and 1 g of molecular sieves (Minipax sorbent - Multisorb) as a desiccant were placed in a 30 ml glass bottle. The bottles were sealed with a Saf-Cap III-A containing HS 035 Heat Seal / 20F as a seal and stored at 40 ° C / 75% relative humidity.

Table 23 Faster stability testing at 40 ° C + 75% rel. humid 0 days 20 days 30 days 40 days 60 days 90 days 120 days 180 days The consignment Solvent P9A483 Ethanol / acetone Lipase, units USP / mg 69.0 67.0 72,4 62.6 64.7 Nd Nd Nd % PM 1,0 0.5 0.2 0.2 0.6 Nd Nd Nd Lipase (loss of activity) -3% 5% -9% -6% Nd Nd Nd P9A485 Ethanol / acetone Lipase, units USP / mg 70.0 73,2 65.7 69.8 66.9 Nd Nd Nd % PM 1,1 0.6 0.3 0.6 0.6 Nd Nd Nd Lipase (loss of activity) 5% -6% 0% -four% Nd Nd Nd P9A486 Ethanol / acetone Lipase, units USP / mg 63.0 61,4 59.7 62 61.5 Nd Nd Nd % PM 1,6 0.2% 0.6% 0.5% 0.4% Nd Nd Nd Lipase (loss of activity) -3% -5% -2% -2% Nd Nd Nd P9A405 Acetone Lipase, units USP / mg 64.0 63,2 62.9 65.1 65.5 64.7 66.7 63.1 % PM 1.3 0.3 0.3 0.3 0.4 0.04 0.6 0.2 Lipase (loss of activity) -one% -2% 2% 2% one% four% -one% P9A476 Acetone Lipase, units USP / mg 64.9 65.3 62.1 62,4 62.6 58.7 67.0 61,4 % PM 1,2 0.4 1,0 1.3 0.5 1,0 1,0 0.6 Lipase (loss of activity) one% -four% -four% -four% -10 % 3% -5% P9A477 Acetone Lipase, units USP / mg 68.7 71.7 68.0 67.2 69.7 64,4 73,4 66,2 % PM 1,1 0.2 0.3 1,0 0,0 0.6 0.7 0.4 Lipase (loss of activity) four% -one% -2% one% -6% 7% -four% ND - no data; PM - mass loss

As shown in table 23, these three samples, upon receipt of which a mixture of ethanol / acetone was used as the coating solvent, showed a similar loss of lipase activity. After 2 months of storage, two of the samples obtained with the acetone coating solvent showed no activity loss, and the third showed a decrease in activity of 4%. This suggests that samples obtained with an acetone coating solvent are more stable than samples prepared with an ethanol / acetone mixture as a coating solvent.

Example 8. Microtablets

To create an additional option, dosage forms with significantly reduced tablet size were prepared. The pancrelipase mixture was tabletted with a round punch with a diameter of 1.5 mm and a bending radius of 1.2 mm.

The pressing parameters were set so as to obtain microtablets ("MT") with a brittleness below 2.5% (USP method). The characteristics of lot 9A402 are given in table 24.

Table 24 Party P9A402 Value Diameter 1.5 mm Mass (20 MT) 0.071 g (0.070-0.073) Thickness (as an average of 20 MT) 1.73 mm (1.70-1.77) Hardness (as an average of 20 MT) 4 N (3-5) Fragility (20 g MT 30 min at 25 rpm) 1.80%

The batch P9A402 was coated in a Glatt-GPCG1 fluidized bed apparatus equipped with a Munters ML 1350 dehumidifier to ensure low moisture content of the air flow (below 1 g / m ³ ). The composition of the suspension is shown in table 2. The coating weight was 22%. Microscopy of film coatings showed that all samples are smooth and homogeneous.

The theoretical composition of the batch P9A422 is shown in table 25.

Table 25 Party P9A422 The composition of the standard shell,% (wt./wt.) MT Pancrelipase 78.00 Hypromellose Phthalate (HP55) 18.34 Triethyl citrate 1.83 Talc 1.83 100,000

Two other batches of microtablets were obtained as described above, and their properties are shown below in table 26.

Table 26 Parameter Party P9A457 Party P9A459 Diameter 1.5 mm 1.5 mm Mass (20 MT) 0.072 g (0.070-0.073) 0.071 g (0.070-0.074) Thickness (average value for 20 MT) 1.73 mm (1.67-1.83) 1.74 mm (1.69-1.82) Hardness (average value for 20 MT) 5 newtons (3-6) 5 newtons (4-6) Fragility (20 g MT, 30 min at 25 rpm) 1.99% 2.02%

Pancrelipase microtablets were coated with one of two suspensions with talc content intermediate between “high” and “low” described above (HP55: CHP: talc = 10: 1: 5), using either acetone or a mixture of ethanol as a solvent in acetone (table 27).

These six tests were performed using a Glatt-GPCG1 fluid bed apparatus equipped with a Munters ML 1350 dehumidifier to ensure low moisture content of the air stream (below 1 g / m ³ ). The coating weight was approximately 22% and microscopy showed that all coatings are smooth and homogeneous.

Table 27 Covered MT Solvent Uncoated MT Party P9A460 Acetone Party P9A402 Party P9A458 Acetone Party P9A457 Party P9A463 Acetone Party P9A459 Party P9A473 Ethanol / acetone Party P9A402 Party P9A466 Ethanol / acetone Party P9A457 Party P9A468 Ethanol / acetone Party P9A459

The theoretical composition of the parties is summarized in table 28.

Table 28 The consignment P9A466 - P9A468 - P9A473, solvent - ethanol / acetone P9A458 - P9A460-P9A463, solvent - acetone Substance Composition,% (wt./wt.) MT Pancrelipase 78.00 78.00 Hypromellose Phthalate (HP55) 13.75 13.75 Triethyl citrate 1.37 1.37 Talc 6.88 6.88 100.00 100.00

HPMC capsules were filled with the coated microtablets described above and packaged in glass bottles containing desiccants (molecular sieves). The bottles were then sealed with a Saf-Cap III-A containing HS 035 Heat Seal / 20F as a seal and stored under accelerated stability testing (40 ° C and 75% relative humidity). Twelve MPMC capsules (5,000 IU lipase dose) and 1 g of molecular sieves (Minipax sorbent Multisorb) as a desiccant were placed in a 30 ml glass bottle. Lipase activity was measured after 20, 30, 40 and 60 days of storage, as shown in tables 29 and 30.

Table 29 Accelerated stability testing at 40 ° C + 75% rel. humidity 0 days 20 days 30 days 40 days 60 days 90 days 120 days 180 days The consignment Solvent P9A466 Ethanol /
acetone Lipase, units USP / mg 64.7 67.0 64.6 63.6 62.3 Nd Nd Nd % PM 1.7 2.2 0.4 0,0 0,0 Nd Nd Nd Lipase (loss of activity) four% 0% -2% -four% Nd Nd Nd P9A468 Ethanol /
acetone Lipase, units USP / mg 61.2 59.6 57.7 58.6 58.9 Nd Nd Nd % PM 1.7 0.5 0.4 0,0 0,0 Nd Nd Nd Lipase (loss of activity) four% 0% -2% -four% Nd Nd Nd P9A473 Ethanol /
acetone Lipase, units USP / mg 59.8 58.9 57.7 59,4 58.4 Nd Nd Nd % PM 1.8 0.7 0.9 0,0 0,0 Nd Nd Nd Lipase (loss of activity) -2% -four% -one% -2% Nd Nd Nd P9A458 Acetone Lipase, units USP / mg 62,4 65,4 64.3 62.9 65.0 62.3 65.5 62.6 % PM 3.0 0.1 0.5 0,0 0,0 0.6 1.3 0.3 Lipase (loss of activity) 5% 3% one% four% 0% 5% 0% P9A460 Acetone Lipase, units USP / mg 56.9 58.2 59.2 58.3 60.0 57.6 62,2 56.8 % PM 1.7 0,07 0.3 0,0 0,0 0,0 0.6 0.2 Lipase (loss of activity) 2% four% 2% 5% one% 9% 0% P9A463 Acetone Lipase, units USP / mg 62.7 63.8 62,2 61.5 59.8 54.5 62.6 58.6 % PM 1,6 2,3 0.5 0,0 0,0 0.4 0.6 0.5 Lipase (loss of activity) 2% -one% -2% -5% -13 % 0% -7% ND - no data; PM - mass loss

Table 30 Accelerated stability testing at 40 ° C + 75% rel. humidity 20 days 30 days 40 days 60 days The consignment Solvent Lipase (loss of activity) P9A466 Ethanol / acetone + 4% 0% -2% -four% P9A468 Ethanol / acetone -3 -four% -four -four% P9A473 Ethanol / acetone -2% -four% -one% -2% P9A458 Acetone + 5% + 3% + 1% + 4% P9A460 Acetone +2 + 4% + 2% + 5% P9A463 Acetone + 2% -one% -2% -5%

All three samples obtained using an ethanol / acetone mixture as a coating solvent showed similar behavior, and after 2 months of storage, the loss of lipase activity was 2-4%. After two months of storage, two samples prepared using an acetone coating as a solvent showed no signs of a decrease in lipase activity, while in a third sample, lipase activity decreased by 5%. Thus, compositions prepared using an acetone coating solvent were more stable than samples prepared using an ethanol / acetone mixture as a coating solvent, which may be related to the water content of the ethanol used.

The microtablets prepared as described above were slightly oblong (see tables 24 and 26); the ratio between the thickness of the microtablets and the diameter ranged between 1.22: 1 and 1.15: 1.

To further reduce the size of microtablets, new samples were prepared with a ratio of thickness to diameter closer to 1: 1 (batch Q9A006), as shown in table 31 below.

Table 31 Parameter Party Q9A006 Diameter 1.5 mm Mass (20 MT) 0.060 g (0.058-0.062) Thickness (average value for 20 MT) 1.50 mm (1.45-1.58) Hardness (average value for 20 MT) 5 N (4-6) Fragility (20 g MT, 30 min at 25 rpm) 1.63%

The batch of Q9A006 was coated with the compositions shown in table 32, the coating weight was 22%. Coating tests were performed using a Glatt-GPCG1 fluidized bed apparatus equipped with a Munters ML 1350 dehumidifier to ensure low moisture content of the air flow (below 1 g / m ³ ).

The theoretical composition of the batch of microtablets coated with Q9A019 was the same as shown in table 28. Microscopy showed that the coatings were smooth and homogeneous.

Table 32 Composition,% (wt./wt.) Substance Intermediate Talc Hypromellose Phthalate (HP55) 7,644 Triethyl Citrate (CHP) 0.764 Talc 3,822 Acetone 87,770 100,000 HP: TPP: talc ratio 10: 1: 5 Total solids 12.23%

The above examples show that digestive enzyme compositions with improved stability can be obtained by maintaining low moisture content and water activity in the components of the composition, for example, by replacing the coating solvent — water ethanol / acetone — with acetone, coating the mini-tablets and microtablets in a stream of dehydrated air (for example, with a moisture content of 0.4-3.6 g / m ³ ). In addition, an increased level of inorganic substances in the coating (for example, the ratio of HP55: TPP: talc in the range from 10: 1: 1 to 10: 1: 5), the choice of less hygroscopic substances for capsules (for example, HPMC or dried HPMC) and improved packaging methods (for example, storage in well-sealed glass bottles containing moisture absorbers) give digestive enzyme compositions and dosage forms with improved stability.

Example 9

The following table 33 shows the accelerated stability testing (in bottles; 40 ° C and 75% relative humidity) of Eudragit coated panrelipase mini-tablets.

Table 33 The consignment one 2 3 four 5 Time months 0 one 0 one 0 one 0 one 0 one Lipase, ME 23030 15510 24180 15810 23550 16014 23000 16100 23613 17594 % (vs time 0) one hundred 67 one hundred 65 one hundred 68 one hundred 70 one hundred 74 Loss of moisture, E (max. 5.0) 4.0 4.9 3.9 4.6 4.2 4.2 3.9 4.3 3.3 3,7

The results show that conventional enteric coatings, for example, Eudragit, do not allow stabilized pancrelipase compositions to be prepared.

Example 10

Examples of dosage forms containing ER coated beads, with a different dose per capsule, are coated on as described in the previous examples, are shown in table 34 below.

Table 34 Content (mg / capsule) for each dose Component Composition 1 Composition 2 Composition 3 Composition 4 Pancrelipase 55.7
(5000 UNITS USP) 108.9
(10,000 UNITS USP) 163.4
(15000 UNITS USP) 217.8
(20,000 UNITS USP) Croscarmellose sodium 1.9 3.6 5.5 7.3 Hydrogenated Castor Oil 0.6 1,2 1.8 2,4 Colloidal silicon dioxide 0.3 0.6 0.9 1,2 Microcrystalline cellulose 3,1 6.1 9.1 12.1 Magnesium stearate 0.3 0.6 0.9 1,2 Hypromellose Phthalate 12,2 18.9 28,4 37.8 Talc 6.1 9.5 14.2 18.9 Triethyl citrate 1,2 1.92 2,8 3.8 Acetone ^b Traces Traces Traces Traces Carrageenan 0.1 0.2 0.3 0.3 Potassium chloride 0.2 0.3 0.4 0.4 Titanium dioxide 2,3 3,5 5.1 5.2 Hypromellose 33.5 52.9 79,4 79.2 Carnauba wax Traces Traces Traces Traces Water 0.38 0.60 0.9 0.90 Yellow iron oxide - 0.1 - 0.2 Red iron oxide - - 0.3 - FDC Blue 2 - - - 0.1

Example 11

The following table 35 shows the water content in containers of various sizes in which are capsules containing the compositions of the present invention. The water content includes the total amount of water from the capsules and the water that has entered the container during storage over a spirit of years. "Equivalent mass of molecular sieves" is the minimum amount of molecular sieves required to absorb the water present in containers.

Table 35 Bottle sizes, cm ³ Number of capsules Capsule weight mg Humidity capsules,% Total water from capsules, mg /
bottle Penetrated water, mg /
2 years/
bottle Equivalent mass of molecular sieves, g thirty 12 95 3% 34 111 0.96 200 one hundred 95 3% 285 401 4,58 750 500 95 3% 1425 474 12.66 thirty twenty 95 3% 57 111 1.12

Example 12

A phase III randomized, double-blind, placebo-controlled crossover study was performed to compare the effects of treatment with the pancrelipase compositions of Table 34 with placebo effects in 34 patients seven years of age and older with cystic fibrosis and ESR. The study was conducted at 14 centers for the treatment of cystic fibrosis in the United States. The primary endpoint of the study was a comparison of the absorption coefficient of fats after oral administration of the pancrelipase composition in daily doses of 10,000 units of lipase or less per kilogram of body weight in combinations of 5,000, 10,000, 15,000 or 20,000 units of lipase per capsule compared to placebo. The secondary endpoints of the study were changes in the nitrogen absorption coefficient as an indicator of the absorption of proteins, cholesterol, fat-soluble vitamins, body weight, body mass index and symptoms of ESR.

Patients receiving these compositions showed a statistically significant increase in fat absorption and nitrogen absorption compared with those receiving placebo; the first group of patients also had fewer symptoms related to malabsorption, such as bloating, flatulence, pain, and stool fat. Patients receiving these pancrelipase compositions also experienced an increase in average cholesterol and vitamin levels compared with patients receiving placebo. A statistically significant decrease was noted in the frequency of bowel movements per day. These compositions were well tolerated by patients, and no serious adverse events were observed during the study.

The average coefficient of fat absorption in percent in patients receiving these compositions was 88.28% versus 62.76% in those taking placebo. The average absorption coefficient of nitrogen was 87.2% versus 65.7% in patients taking placebo, and the average number of bowel movements per day decreased in the corresponding groups of patients from 2.66 to 1.77.

Example 13

A pediatric clinical trial of phase III was performed to evaluate the effect of treatment with the compositions of table 34 in an open study involving 19 patients with cystic fibrosis under 7 years old in 11 centers for the treatment of cystic fibrosis in the United States - the first test of pancreatic replacement therapy of this size, conducted with the participation of young children with exocrine pancreatic insufficiency. The study design envisaged a seven-day period of dose stabilization followed by a seven-day treatment period; patients received 5000 units of lipase per capsule daily; the drug was sprinkled with food. The primary endpoint of the study was the percentage of “responders to treatment,” or patients without excess fat in feces and without malabsorption after one or two weeks of treatment. Secondary endpoints included changes in body weight, nutritional status, frequency and consistency of the stool and the frequency of bloating, pain and flatulence, as well as the weakening of clinical symptoms, according to the doctor and parent or guardian. Product safety was also evaluated.

The average percentage of responders to treatment, as defined in the study protocol, during screening (the beginning of the stabilization period when patients received previous replacement therapy with pancreatic enzymes before treatment) was 52.6%. At the end of the stabilization period and at the end of the treatment period, the average percentage of respondents to treatment was 66.4 and 57.9%, respectively. Symptoms of malabsorption were significantly less pronounced at the end of the treatment period than with screening, which was consistent with the observation regarding the control of symptoms of malabsorption noted in the phase III study described in Example 12 above. Pancrelipase compositions of the present invention were also well tolerated by patients, and severely undesirable phenomena during the study were not observed.

These results demonstrate that the compositions of the present invention effectively control the symptoms of malabsorption, and are consistent with the results obtained in a phase III pilot study described in Example 12. A statistically significant number of doctors and patients noted that symptom control was better with the compositions of the present invention. than against the background of previous therapy.

Example 14

An open, randomized, single-center, non-comparable, phase III crossover study was performed to compare the effects of treatment with pancrelipase compositions from Table 34 to determine the gastrointestinal bioavailability of these compositions in 10 patients with chronic pancreatitis with exocrine pancreatic insufficiency. Proton pump inhibitors, antacids, and drugs that can affect gastrointestinal motility were canceled 7 days before the start of the study. Patients were randomized to receive either only Ensure Plus ™ (a dietary supplement with vitamins supplied by Abbott) or Ensure Plus ™ in combination with 75,000 units of USP lipase (3 capsules containing 20,000 units each plus 3 capsules containing 5,000 units each) per procedure . The capsules were opened and their contents mixed with 480 ml of Ensure Plus ™ immediately before administration. After a one-day “wash” period, patients who previously received only Ensure Plus ™ received Ensure Plus ™ in combination with 75,000 IU USP lipases, and patients who previously received a combination of Ensure Plus ™ and lipase received only Ensure Plus ™. The next day, a physical examination was performed on the patients, and blood and urine samples were taken from them. The bioavailability of the compositions of the present invention was assessed by the number of corresponding enzymes (i.e. lipase, amylase and chymotrypsin) released and secreted into the duodenum after administration of the composition in the presence of Ensure Plus ™. In addition, the level of cholecystokinin in the blood was measured, as well as the pH of the gastric and duodenal contents. Lipase activity was measured according to the method of Carriere, F .; Barrowman, J.A .; Verger, R .; Laugier, R. Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans. Gastroenterology 1993, 105, 876-88. Amylase and chymotrypsin were measured according to the method described in Carriere, F .; Grandval, P .; Renou, C .; Palomba, A .; Prieri, F .; Giallo, J; Henniges, F .; Sander-Struckmeier, S .; Laugier, R. Quantitative study of digestive enzyme secretion and gastrointestinal lipolysis in chronic pancreatitis Clin. Gastroenterol. Hepatol. 2005, 3, 28-38.

It was found that treatment with the pancrelipase compositions of the present invention results in the release of a statistically significantly greater amount of amylase, lipase and chymotrypsin into the duodenum of patients who received a combination of Ensure Plus ™ and pancrelipase compared to patients who received only Ensure Plus ™ (after correction according to pH as an interfering factor).

The average bioavailability of lipase, amylase, and chymotrypsin for the eight patients who completed the protocol study was 27.5%, 21.6%, and 40.1%, respectively. It was found that patients come in two different subpopulations of gastrointestinal pH (“normal pH” and “low pH”). In patients with “normal pH” (that is, patients whose duodenal pH averaged over 4), the average bioavailability of lipase, amylase and chymotrypsin was higher than for the entire study group: 45.6%, 26.9% and 47, 7% respectively. No differences in cholecystokinin levels between the two subpopulations were observed.

Since the bioavailability of lipase, amylase and chymotrypsin in patients with "normal pH" and "low pH" is different (especially lipases), the effectiveness of the pancrelipase compositions or dosage forms of the present invention can be increased, for example, in patients with "low pH", due to the simultaneous administration of drugs that increase the pH of the gastrointestinal tract, for example, proton pump inhibitors and antacids. However, the compositions or dosage forms of the present invention can be administered without the simultaneous administration of, for example, proton pump inhibitors.

The preceding description of the invention is given for the purpose of illustration and description. This description should not be construed as an exhaustive or limiting invention in the exact form disclosed. In light of the above ideas, modifications and changes are possible. Descriptions of embodiments have been selected to explain and describe the principles of the present invention and its practical application, and are not intended to limit the scope of the claims.

All publications and patents or patent applications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application were specifically and individually incorporated by reference.

Claims (47)

1. A composition for treating or preventing a digestive enzyme deficiency disorder comprising a plurality of coated particles, each particle comprising an enteric coated core, wherein the core comprises pancrelipase and where the enteric coating comprises: 10-20 wt.% at least one enteric-soluble polymer and 4-10 wt.% talc, where the indicated wt.% are calculated from the total weight of the coated particles and where the coated particles exhibit a loss of enzymatic activity of pancrelipase no more than about 25% after 6 months accelerated stability testing. 2. The composition according to claim 1, where the moisture content is approximately 3% or less. 3. The composition according to claim 1, where the composition has a water activity of approximately 0.6 or less. 4. The composition according to claim 2, where the moisture content is approximately 2% or less. 5. The composition according to claim 1, where the coated particles show a loss of the enzymatic activity of pancrelipase of not more than approximately 15% after 6 months of accelerated stability testing. 6. The composition according to claim 1, where the coating further comprises at least one plasticizer. 7. The composition according to claim 6, where the coating further comprises 1-2 wt.%, At least one plasticizer based on the total weight of the coated particles. 8. The composition according to claim 7, where the plasticizer is selected from the group consisting of triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacinate, polyethylene glycol, polypropylene glycol, castor oil, acetylated monoglyceride dichloride glyceride. 9. The composition of claim 8, where the plasticizer is triethyl citrate. 10. The composition according to claim 1, where the core further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, disintegrant, lubricant, glidant, diluent and mixtures thereof. 11. The composition of claim 10, where the binder is selected from the group consisting of starches, sugars, lactose, sugar alcohols, xylitol, sorbitol, maltitol, cellulose, microcrystalline cellulose, modified cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, alginic acid and polyvinyl vinyl; the baking powder is selected from the group consisting of dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, corn starch, alginic acid, hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose cellulose, crosslinked sodium carboxymethyl cellulose cellulose cellulose cellulose cellulose, cellulose, sodium carboxymethyl starch, sodium starch glycolate, starches and rice starch;
a lubricant is selected from the group consisting of calcium stearate, magnesium stearate, sodium stearyl fumarate, stearic acid, zinc stearate, talc and waxes;
the glidant is selected from the group consisting of colloidal silicon dioxide and talc; and
the diluent is selected from the group consisting of mannitol, sucrose, anhydrous dibasic calcium phosphate, anhydrous dihydrate dibasic calcium phosphate, tribasic calcium phosphate, cellulose, lactose, magnesium carbonate and microcrystalline cellulose. 12. The composition of claim 10, where the core further includes
1-4 wt.%, At least one baking powder;
0.2-0.6 wt.%, At least one glidant;
2-6 wt.%, At least one binder and
0.2-0.6 wt.%, At least one lubricant calculated on the total weight of the coated particles. 13. The composition of claim 12, wherein the at least one disintegrant is crosslinked croscarmellose sodium, the at least one glidant is colloidal silicon dioxide, the at least one binder is microcrystalline cellulose, and the at least one lubricant is magnesium stearate. 14. The composition according to item 12, where the core further comprises 0.5-1.0 wt.%, At least one plasticizer, based on the total weight of the coated particles. 15. The composition of claim 14, wherein the at least one plasticizer is hydrogenated castor oil. 16. The composition according to claim 1, where the core comprises 68-90 wt.% Pancrelipase. 17. The composition according to claim 1, where the pancrelipase is obtained from a pig. 18. The composition according to claim 1, where the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, copolymers of methacrylic acid and methyl methacrylate and shellac. 19. The composition of claim 18, wherein the enteric polymer is hydroxypropyl methyl cellulose phthalate. 20. The composition according to any one of claims 1 to 19, where pancrelipase has a ratio of protease activity to lipase activity from about 1.8 to about 6.2. 21. The composition according to any one of claims 1 to 19, where pancrelipase has a ratio of protease activity to lipase activity from about 2.0 to about 6.1. 22. The composition according to any one of claims 1 to 19, where pancrelipase has a ratio of amylase activity to lipase activity from about 1.8 to about 8.2. 23. The composition according to any one of claims 1 to 19, where pancrelipase has a ratio of amylase activity to lipase activity from about 2.0 to about 8.2. 24. The composition according to any one of claims 1 to 19, where pancrelipase has a lipase: protease: amylase activity ratio of from about 1:10:10 to about 10: 1: 1. 25. The composition according to any one of claims 1 to 19, wherein the pancrelipase has a combined lipase, protease, and amylase activity of about 4500-5500 ME of lipase activity, about 8000-34000 ME of protease activity and about 8000-45000 ME of amylase activity;
approximately 9000-11000 ME of lipase activity, approximately 17000-67000 ME of protease activity and approximately 17000-90000 ME of amylase activity;
approximately 13500-16500 ME of lipase activity, approximately 26000-100000 ME of protease activity and approximately 26000-135000 ME of amylase activity or
approximately 18000-22000 ME of lipase activity, approximately 35000-134000 ME of protease activity and approximately 35000-180000 ME of amylase activity. 26. The composition according to any one of claims 1 to 19, where the core of the coated particles has a nominal particle diameter in the range of about 2-5 mm and a coating weight of the coated particles of about 15% based on the total weight of the coated particles. 27. The composition according to any one of claims 1 to 19, where the core of the coated particles has a nominal particle diameter in the range of about 1-2 mm and a coating weight of the coated particles of about 22% based on the total weight of the coated particles. 28. A dosage form for treating or preventing a disorder associated with a digestive enzyme deficiency, comprising a composition according to any one of claims 1-19. 29. The dosage form of claim 28, wherein said dosage form is a capsule filled with a composition. 30. The dosage form according to clause 29, where the capsule consists of a material selected from the group consisting of cellulosic polymer, hydroxypropylmethyl cellulose, starch, polysaccharide, pullulan and gelatin. 31. The dosage form of claim 30, wherein the capsule consists of hydroxypropyl methyl cellulose having a moisture content of about 6% or less. 32. The dosage form according to p, where the capsule consists of hydroxypropyl methylcellulose having a moisture content of approximately 2% or less. 33. The dosage form according to p, where the specified dosage form has essentially zero overflow. 34. A package containing a sealed container of moisture-proof material, a desiccant and at least one dosage form according to claim 28, where the composition has a moisture content of about 3% or less, and where the desiccant and at least one dosage form are inside airtight container. 35. The packaging according to clause 34, where the moisture-proof material is selected from the group consisting of metal, glass, plastic and metal-coated plastic. 36. The packaging according to clause 34, where the desiccant is selected from the group consisting of a molecular sieve, clay, silica gel, activated carbon, and combinations thereof. 37. The packaging of claim 36, wherein the desiccant is a molecular sieve. 38. The packaging according to clause 34, where the specified dosage form is a capsule consisting of hydroxypropyl methylcellulose. 39. The use of a composition according to claim 1 for the manufacture of a medicament for the treatment or prevention of a disorder associated with a deficiency of digestive enzymes in mammals in need thereof. 40. The use of claim 39, further comprising using a drug that increases the pH of the gastrointestinal tract, and where the pancrelipase composition and a drug that increases the pH of the gastrointestinal tract are in the same composition or in different compositions. 41. The use of claim 40, wherein the drug is selected from the group consisting of proton pump inhibitors and antacids. 42. The use of claim 39, wherein the disorder is cystic fibrosis. 43. The use of claim 39, wherein the disorder is a malabsorption of fats in a mammal. 44. The application of clause 39, where the drug increases the absorption coefficient of fat in the patient. 45. The method of producing a pancrelipase composition according to claim 1, comprising: applying to the pancrelipase particles in an atmosphere with a moisture content of approximately 3.6 g of water per cubic meter or less of a coating containing an enteric polymer and talc with the formation of a plurality of particles with a delayed release. 46. The method according to item 45, where the particles are coated with a mixture of an enteric polymer dissolved in acetone and talc. 47. The method of claim 45, wherein the multiple delayed-release particles have a moisture content of about 3% or less or water activity of about 0.6 or less, and where the loss of digestive enzyme activity after 6 months of accelerated stability testing is not more than 15%.