KR100355060B1 - How to prepare a solid pharmaceutical dosage form - Google Patents

Abstract

The present invention relates to a method for preparing a rapidly disintegrating oral solid dosage form of a pharmaceutically active substance having an unacceptable taste, which method has an unacceptable taste with a water soluble or water soluble carrier material. Forming a solution or suspension in a solvent in the form of a pharmaceutically active substance that is soluble in water rather than in form, and has a better taste to taste, forming a suspension or separation unit of the solution, and a pharmaceutically active substance Removing the solvent from the separation unit under conditions that form a reticulum of the carrier material that carries a dosage in a form that is less soluble and has a better taste.

Description

How to Prepare a Solid Pharmaceutical Dosage Form

The present invention relates to a method for preparing a solid pharmaceutical dosage form, in particular a method for preparing a rapidly unhappy oral solid dosage form of a pharmaceutically active ingredient having an unacceptable taste in humans or animals.

Many pharmaceutically active ingredients are provided for oral use in the form of tablets, pills or capsules. Tablets, pills or capsules generally need to be swallowed with water so that the pharmaceutically active ingredient can be absorbed through the gastrointestinal tract. For some patients, swallowing tablets, pills or capsules is difficult or impossible, especially for pediatric patients and geriatric patients. In addition, attempts to administer tablets to non-human animals that may be uncooperative in taking tablets, pills, or capsules often face similar difficulties.

GB-A-1548022 and GB-A-2111423 describe oral solid pharmaceutical dosage forms which disintegrate rapidly in the oral cavity and methods for their preparation. Solid dosage forms as disclosed include open matrix reticular tissue with a pharmaceutically active ingredient, which open matrix comprises a water soluble or water-dispersible carrier material that is inert to the pharmaceutically active ingredient. . Solid dosage forms are prepared by subliming or removing the solvent from a solution or suspension comprising the pharmaceutically active ingredient and a carrier material. Sublimation or removal of the solvent is preferred to be carried out by freeze drying.

Other methods of preparing oral solid pharmaceutical dosage forms that disintegrate rapidly in the oral cavity are described in US-A-5039540, US-A-5120549, US-A-5330763, PCT / JP93 / 0163l and PCT / US93 /. 12566.

Solid dosage forms produced by these various methods quickly disintegrate upon entering the patient's mouth, delivering a pharmaceutically active ingredient in the desired dosage.

Although overcoming the problem of swallowing tablets, pills, or capsules in a solid dosage form as described above, the patient will taste the pharmaceutically active ingredient as the dosage form disintegrates. For some pharmaceutically active ingredients, if the taste is slightly unpleasant, sweetening or flavoring agents that block this taste may be used to make the unpleasant taste acceptable. However, for some pharmaceutically active ingredients, despite the use of sweetening and flavoring agents, there will still be an unpleasant product which reduces the patient's compliance.

The present inventors have developed a method for producing a rapidly disintegrating oral solid dosage form of a pharmaceutically active ingredient having an unacceptable taste, instead of relying on efforts to hide unacceptable tastes by using sweeteners, flavors and the like. It was.

Accordingly, the present invention provides a method for preparing a rapidly disintegrating oral solid dosage form of a pharmaceutically active ingredient with an unacceptable taste, which, together with a water soluble or water soluble carrier material, has an unacceptable taste. Forming a solution or suspension of the solvent in the form of a pharmaceutically active ingredient that is less soluble than the form having it, forming individual units of the solution or suspension, and administering the unit in a less soluble form of the pharmaceutically active ingredient Removing the solvent from the individual units under conditions that form a network of amounts of carrier material.

As used herein, the expression “quickly disintegrating” refers to solid dosage forms described in the Disintegration Test for Tablets, B.P. 1973, and disintegrate in water within 60 seconds, preferably 5 to 10 seconds at 37 ° C. when tested by the following method described in British Patent No. 1548022.

Device

Glass with a disk of rustproof wire gauze with a length of 80 to 100 mm, an inner diameter of about 28 mm, an outer diameter of 30 to 31 mm and according to the requirements for the number 1.70 sheave at the lower end to form a basket or Suitable plastic tube (BP 1973 page A136).

A glass cylinder having a flat bottom at a temperature of 36 to 38 ° C., having an inner diameter of about 45 mm and containing a depth of 15 cm or more.

The basket was suspended in the center of the cylinder so that it could be repeatedly raised and lowered in a consistent manner, with the gauze scattering the surface of the water at the highest position and keeping the basket's upper rim at the lowest position.

Way

One molded article is placed in a basket and raised and lowered in a manner that repeats the complete ascending and descending movements at a speed equivalent to 30 times per minute. When no particles remain on the gauze that do not pass easily through the gauze, the molded article disintegrates.

Upon oral administration of a solid dosage form of the invention to a patient, the pharmaceutical dosage form disintegrates rapidly in the oral cavity.

The rapidly disintegrating oral solid dosage forms of the present invention provide a pharmaceutical active ingredient with an unpleasant taste without sacrificing the bioavailability of the pharmaceutically active ingredient compared to currently available dosage forms containing more soluble compounds. This makes it possible to provide good form. The pharmaceutically active ingredient is provided in a less soluble form, allowing the solid dosage form to taste less of the medicament as it is dissolved / disintegrated into saliva.

Pharmaceutically active ingredients with an unacceptable taste may be provided in a less soluble form prior to forming the solution or suspension. Alternatively, the pharmaceutically active form can be converted to a less soluble form while performing the method of the invention, for example during the preparation of a solution or suspension.

A pharmaceutically active ingredient with an unacceptable taste may be used to convert salts into free acids or free bases, to change salt forms, to form hydrates, to change the polymorphic form of such hydrates, or to any other suitable means. Can be made less soluble.

The individual units of suspension or solution may be in the form of, for example, liquid units, solid units, for example frozen units, or gelled units in which the carrier material readily forms a gel, contained in a pocket of a suitable mold.

Removal of the solvent from the individual units of the solution or suspension comprising the less active form of the pharmaceutically active ingredient and the water-soluble or hydrated carrier material is carried out by techniques well known to those skilled in the art.

If the individual units are in liquid form, they will generally be frozen or gelled before they are precursored.

Liquid solutions or suspensions that may be contained in the pockets of suitable molds may, for example, pass a gaseous cooling medium, such as liquid nitrogen, over the mold, insert the mold into a nitrogen spray freezer, or place the mold on a cooled surface. Freeze by cooling through. Once the dosage form is frozen, the mold can be stored in a cold reservoir before it is dried. Frozen individual units can be dried by freeze drying according to techniques well known to those skilled in the art. The solvent is sublimed into a freeze drying process which converts the solid solvent directly into steam under reduced pressure. The freeze drying process will typically be carried out in a freeze drying chamber operating under a vacuum of 0.1 to 1.0 mBar for a time of 180 to 500 minutes.

Alternatively, the frozen individual units can be dried by methods as described in US Pat. Nos. 5,120,549 and 5330763. In this method, the pharmaceutically active ingredient and the carrier material dispersed in the first solvent are coagulated and the coagulated matrix is subsequently mixed with a second solvent which can be substantially miscible with the first solvent at a temperature below the freezing point of the first solvent. In contact, the matrix component is substantially insoluble in the second solvent such that the first solvent is removed from the matrix.

Another alternative method for drying frozen individual units is described in WO 94/14422. In this method, the solvent is removed under conditions that evaporate the solvent from the solid through the liquid state to gas, rather than sublimating the solid into a gas as in lyophilization. This is accomplished by vacuum drying at temperatures below the equilibrium freezing point of the composition which phase changes the solvent (eg water).

If the individual units are gelled units, any drying method that does not affect the properties of the preparation can be used. For example, drying may be carried out under reduced pressure or by forced air drying. Drying under reduced pressure is preferably carried out at 25 to 35 ° C. for 2 to 5 hours under a vacuum of -750 mmHg or less, whereas drying using forced air drying is performed at 3 to 15 ° C. for 1 to 6 days. desirable.

The solvent used to form a solution or suspension of the pharmaceutically active ingredient is preferred for water, but may be mixed with an auxiliary solvent such as an alcohol if it is desired to improve the solubility of the active ingredient.

The carrier material used to form the network tissue containing the pharmaceutically active ingredient may be any pharmaceutically acceptable, inert to pharmaceutically active ingredient, capable of forming a rapidly disintegrating network tissue. It may be a water soluble or a hydratable material. Preferred carrier materials for use in the present invention are gelatin, preferably pharmaceutical grade gelatin.

In addition, other substances such as hydrolyzed dextrose, dextran, dextrin, maltodextrin, alginate, hydroxyethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, corn-syrup solids, pectin, Carrageenan, daikon radish, chitosan, locust bean gum, xanthan gum, guar gum, acacia gum, tragacanth, konjac flour, rice flour, wheat Gluten, sodium starch glycolate, soy fiber protein, potato protein, papain, horseradish peroxidase, glycine or mannitol can be used.

The suspension or solution prepared according to the method of the present invention is preferably an oral dosage form which is formed into individual units by introducing into a mold each comprising a plurality of depressions corresponding to the desired shape and size. desirable. The mold preferably includes a number of depressions formed from sheets of film material that may be similar to the materials commonly used in blister packaging of medicaments. WO 94/12142 describes particularly preferred film materials for use as molds in the present invention. The desired amount of suspension or solution can be filled into the mold using automatic filling means that deliver a predetermined amount to each depression in the mold.

The covering material may be adhered to the film material in the area surrounding the depression after removing the solvent from the solution or suspension filling the depression. The covering sheet is preferably aluminum foil or an aluminum foil laminate, which can be adhered to the film material around the depression, for example by a heat sensitive material. The covering sheet may be peeled off by the user so that it does not cover the oral dosage form within the moiety in the mold, or alternatively, it may be adhered to the film material in a manner that makes it suitable for pushing the oral dosage form. Can be.

Another method of forming frozen or gelled individual units of a solution or suspension involves solidifying the mixture in droplet form. For example, a solution or suspension can be passed through one or more holes to form droplets, spheres or sprays of small particles that can solidify by passing through a cooling gas or liquid, such as liquid nitrogen. Alternatively, the drops, spheres, or sprays cannot be mixed with the solution or suspension, and as the droplet solidifies, it falls with the cooled liquid having a density such that it falls through the immiscible liquid or floats on the surface of the immiscible liquid. It can solidify in contact.

In addition, suspensions or solutions prepared according to the methods of the present invention may contain other additional ingredients such as colorants, flavors, sweeteners or preservatives, or fillers such as mannitol or sorbitol to improve the physical properties of oral dosage forms.

The methods of the present invention can be used to prepare rapidly disintegrating oral solid dosage forms of various pharmaceutically active ingredients with an unacceptable taste. For example, for formulation into rapidly disintegrating oral dosage forms, loperamide is incorporated into conventional tablets in the form of hydrochloride with an unacceptable taste. However, using loperamide in free base form can result in a tasty dosage form. Similarly, for formulation into rapidly disintegrating oral dosage forms, domperidone is incorporated into conventional tablets in the form of maleates with an unacceptable taste. However, the use of domperidone in the form of a free base can result in a tasty dosage form.

The advantage of using less soluble forms of the pharmaceutically active ingredient in the process of the invention is that the less soluble forms are generally easier to lyophilize, vacuum dry or typically dry.

The method of the present invention for preparing faster disintegrating oral dosage forms that are better for taste does not require the use of expensive pharmaceutical coating techniques or complexation techniques to mask the taste of the pharmaceutically active ingredient.

Also included within the scope of the present invention are rapidly disintegrating oral solid dosage forms prepared according to the methods of the present invention.

Thus, within the scope of the present invention, a rapidly disintegrating oral solid dosage form of a pharmaceutically active ingredient that enhances taste by a method as described above is included.

The invention will be further described with reference to the following examples.

Example 1

Rapidly disintegrating oral solid dosage forms of leperamide were prepared from loperamide hydrochloride as follows:

Gelatin was added to the water in the mixing vessel and mixed while heating to about 40 ° C. The mixture was mixed under vacuum and homogenized until the gelatin completely dissolved.

Gelatin solution was added to the mixture of mannitol, sodium bicarbonate and loperamide hydrochloride, and the mixture was mixed and homogenized until the soluble components dissolved and the drug particles were completely dispersed. The mixture was cooled under vacuum and aspartame and peppermint flavourant were added.

The suspension was administered into blister pockets, frozen and pre-frozen to produce the final dosage form.

During the treatment, loperamide hydrochloride was converted to the less soluble loperamide free base form by sodium bicarbonate buffer.

The product had an acceptable taste.

Example 2

Maleic acid domperidone is a pharmaceutical compound with an unpleasant taste and, when formulated into a rapidly disintegrating oral dosage form that is initially lyophilized, produces an unacceptable product.

Domperidone is formulated in the form of a free base (which is less soluble in water or saliva than maleic acid domperidone) and in a solid oral dosage form that disintegrates rapidly using the following ingredients.

A solution containing gelatin and mannrol was prepared and aspartame and peppermint flavourant were added to the solution. An aliquot of the final solution was added to the domperidone powder and a paste formed upon stirring. The rest of the solution was added and a homogeneous suspension was obtained. The suspension was dispensed in 150 mg aliquots into the pockets of the blister packs, frozen and lyophilized to produce the final dosage form. The product tasted acceptable.

Claims (15)

A method for preparing a rapidly disintegrating oral solid dosage form of a pharmaceutically active ingredient with an unacceptable taste, Less soluble in water than the corresponding salt form having an unacceptable taste, together with a carrier material selected from the group consisting of water soluble mid-hydratable carrier materials, and compounds which convert the pharmaceutically active ingredient present in salt form into the free base form Forming a system selected from the group consisting of an aqueous solution or a suspension of an aqueous medium in an uncoated and uncomplexed form of a pharmaceutically active ingredient which is present in the form of a more preferred free base; Forming individual units of the system, and Removing the aqueous medium from the individual units under conditions such that reticular tissue of a carrier material having a dosage of a less soluble, tasteless, uncoated, complexed form of the pharmaceutically active ingredient is formed. The method of claim 1 wherein the aqueous solution comprises water. The method of claim 2 wherein the aqueous medium contains an auxiliary solvent. The method of claim 1 wherein the carrier material is gelatin. The method of claim 1 wherein the individual units are selected from the group consisting of liquid units, frozen units and gelled units. 6. A method according to claim 5, wherein the individual units are formed in a mold comprising a plurality of pockets. 6. The method of claim 5, wherein the individual units are frozen liquid units before removing the aqueous medium. The method of claim 1 wherein the unit is a frozen unit and the aqueous medium is removed by freeze drying. 6. The method of claim 5, wherein the unit is a frozen unit and the frozen matrix comprising the aqueous medium, the pharmaceutically active ingredient and the carrier material is brought into contact with a solvent that is substantially miscible with the aqueous medium at a temperature below the freezing point of the aqueous medium. Wherein the aqueous medium is removed by removing the aqueous medium from the matrix. 6. The method of claim 5, wherein the unit is a frozen unit and the aqueous medium is removed by vacuum drying under conditions in which the aqueous medium is evaporated from the frozen unit into the gas through a liquid state. A process according to claim 5, wherein the individual units are gelled units from which the aqueous medium is removed by drying under conditions selected from the group consisting of reduced pressure and forced air drying. 7. The method of claim 6, wherein the mold comprises one or more depressions in the sheet of film material. 13. The method of claim 12, wherein the sheet of covering material adheres to the film material at one or more areas around the depression after removing the aqueous medium from the system. A method for preparing a rapidly disintegrating oral solid dosage form of a pharmaceutically active substance having an unacceptable taste, Uncoated of a pharmaceutically active ingredient present in free base form which is less soluble in water and tastes better than the corresponding salt form having an unacceptable taste, together with a carrier material selected from the group consisting of water-soluble and water-soluble carrier materials. Forming a system selected from the group consisting of an aqueous solution or a suspension of an aqueous medium in an uncomplexed form; Forming individual units of the system, and Removing the aqueous medium from the individual units under conditions such that a reticulum of the carrier material is formed having a dosage of a less soluble and tasteless uncoated and complexed form of the pharmaceutically active ingredient, Wherein the pharmaceutically active ingredient is loperamide hydrochloride which is converted into the form of loperamide free base during the manufacture of the system. A method for preparing a rapidly disintegrating oral solid dosage form of a pharmaceutically active substance having an unacceptable taste, Uncoated of a pharmaceutically active ingredient present in free base form which is less soluble in water and tastes better than the corresponding salt form having an unacceptable taste, together with a carrier material selected from the group consisting of water-soluble and water-soluble carrier materials. Forming a system selected from the group consisting of an aqueous solution or a suspension of an aqueous medium in an uncomplexed form; Forming individual units of the system, and Removing the aqueous medium from the individual units under conditions such that a reticulum of the carrier material is formed having a dosage of a less soluble and tasteless uncoated and complexed form of the pharmaceutically active ingredient, The less soluble pharmaceutically active ingredient is a free domperidone base.