JP2010209108A - Tablet formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a tablet formulation for cough/cold controlled of release and absorption to secure a predetermined release rate and more effective tablet formulation by accurately controlling release of multiple effective ingredients. <P>SOLUTION: The tablets for cough/cold controlled of release and absorption include tablet cores including multiple effective ingredients, particularly an antihistaminic agent, a decongestive agent and an antitussive agent together with a pharmaceutically acceptable excipient. The peculiar permeable membrane includes at least one effective ingredient surrounding and present in the cores wherein the membrane includes a large amount of structural components impermeable to respective effective ingredients and a small amount of structural components allowing the controlled release and absorption rate possible for each effective ingredient and the pharmaceutically acceptable excipient when the tablets are placed in an aqueous environment. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to controlled release pharmaceutical formulations, and in particular to controlled release cough / cold tablet formulations containing a number of active ingredients. Related.

  Numerous active ingredient-containing preparations are known, in particular preparations for the treatment of common colds and influenza. Such formulations reduce relief from symptoms such as nasal and sinus congestion, colds, sneezing, fever, mild sore throat, pain, body pain, and hay fever and other respiratory allergies. Is a proven and effective way to give Such formulations are conventional immediate release formulations. Numerous active ingredient-containing preparations effective in reducing the above-mentioned range of symptoms have not been obtained so far in preparations with controlled release and absorption.

  Thus, Belgian Patent No. 900,824 discloses the release of potassium chloride, which represents about 66% by weight of the total tablet weight, through a unique permeable membrane surrounding the tablet core. A controlled tablet formulation is disclosed.

  GB-A 2218905 describes the potassium chloride component of a tablet present in an amount of at least 80% by weight of the tablet through a unique permeable membrane surrounding the tablet core. A controlled release tablet formulation for release is disclosed.

Tablet formulations with controlled release of a single active ingredient are known in which the active ingredient is released through a unique permeable membrane surrounding the tablet core.
As used herein, the term “cough / cold” refers to nasal and sinus congestion, colds, sneezing, fever, mild sore throat, pain, body pain, and hay fever and other respiratory allergies. It is intended to encompass symptoms.

  Cough / cold tablets with controlled release and absorption containing multiple active ingredients that can accurately control the release of multiple active ingredients to ensure a predetermined release rate and more effective tablet formulation. It is an object of the present invention to provide formulation improvements.

  Accordingly, the present invention provides a tablet core containing a number of active ingredients together with a pharmaceutically acceptable excipient, and a unique comprising at least one active ingredient surrounding the core and present in the core. Permeable membranes, which contain large amounts of components that are impermeable to each active ingredient and each active that is present in the core when the tablet is placed in an aqueous environment. Release and absorption, characterized in that the ingredients and pharmaceutically acceptable excipients contain small amounts of components allowing them to exit at a rate that allows their controlled release and absorption A controlled cough / cold tablet formulation is provided.

  In one embodiment, the unique permeable membrane includes a water-soluble component that is permeable to each active ingredient and a water-insoluble component that is impermeable to each active ingredient. The components dissolve when the tablet is placed in an aqueous environment, and each active ingredient and pharmaceutically acceptable excipient present in the core allows their controlled release and absorption. It causes the generation of holes that allow it to exit at speed.

  Preferably, the active ingredients in the tablet core include an antihistamine, an antihypertensive and a kind of cough suppressant. Most particularly, the tablet core includes an antihistamine, a decongestant and two cough suppressants.

  In a preferred embodiment, the tablet core includes chlorpheniramine maleate, phenylpropanolamine hydrochloride, dextromethorphan hydrobromide and noscapine hydrochloride.

  The tablet core may also include one or more highly soluble components that cause a liquid flow from the core in an aqueous environment. This highly soluble ingredient can be a number of active ingredients themselves or each active ingredient itself, but also suitably potassium chloride, sodium bicarbonate, sodium citrate, sodium carbonate, citric acid, fumaric acid, apple It can be acid, succinic acid or tartaric acid or mixtures thereof.

  Chlorpheniramine maleate is an antihistamine and helps to reduce sneezing, colds and itching of the eyes, nose and throat. Chlorpheniramine maleate appears to be less lethargic than with many other antihistamines, and this chlorpheniramine maleate is the most appropriate of these types of drugs for daytime use. One.

  Phenylpropanolamine hydrochloride is a decongestant that facilitates free breathing by helping to reduce nasal passages and sinus hyperemia. This hydrochloride salt does not appear to produce the side effects associated with CNS (central nervous system) stimulation as do other drugs of the same class.

  The use of the two cough suppressant compounds, dextromethorphan hydrobromide and noscapine hydrochloride, provides additional benefits but avoids the side effects associated with increasing doses of either compound. Is done. These compounds are admixed with the intention of reducing coughing, persistent coughing, non-wetting coughing and under the conscious control to induce coughing reflexes. Both dextromethorphan hydrobromide and noscapine hydrochloride act according to central function and do not produce euphoria or drowsiness, and are unlikely to be dependent.

  Combining the four active ingredients in a single dosage form that controls release and absorption provides the most effective means of combating symptoms associated with cough and cold. Conventional immediate release cough / cold therapy by a single tablet formulation with controlled absorption designed to target the majority of the symptoms encompassed by the present invention by the term “cough / cold” In addition, there are advantages over combination therapy with controlled absorption that does not contain all of the four components.

By using a membrane barrier that gives effectively programmed control over the release rate of the four active ingredients from the tablet core, the dimensions of the dosage form are maintained at just acceptable limits, and the tablet intake To ensure the ease. The release rate of each active ingredient is a rate that does not irritate the gastric mucosa, and this rate is suitably the following dissolution distribution when measured in water according to the paddle method described in the US Pharmacopeia XXI:
(A) 15-40% of each active ingredient is released in the measurement after 1.5 hours,
(B) 35 to 65% of each active ingredient is released in the measurement after 3 hours, and (c) 75% or more of each active ingredient is released in the measurement after 6 hours. Is measured in vitro as the dissolution rate corresponding to.

  Preferably, the formulation comprises four ingredients, chlorpheniramine maleate, phenylpropanolamine hydrochloride, dextromethorphan hydrobromide and noscapine hydrochloride, approximately 0.1: 1: 0.7: 0. .7 in a weight ratio. A typical tablet has the following composition:

  For the immediate release of the active ingredient for the on-set of action following the administration of the tablet, at least one, preferably two or more of the active ingredients are contained in the membrane in a total active ingredient per tablet. Preferably it has a concentration of about 10% of the concentration.

  Thus, according to a preferred embodiment of the present invention, the active ingredient, chlorpheniramine maleate, phenylpropanolamine hydrochloride, dextromethorphan hydrobromide and noscapine hydrochloride are pharmaceutically acceptable excipients. And a unique permeable membrane surrounding the core containing the active ingredients, chlorpheniramine maleate, dextromethorphan hydrobromide and noscapine hydrochloride A controlled release and absorption tablet formulation is provided.

  The tablet core is preferably manufactured using a dry blend direct compression technique that provides a tablet core that is non-friable and hard enough to withstand the application of a specific permeable membrane.

Preferably, the hardness is at least 40 newtons and no more than 1.0 wt% friability.
The thickness of the specific permeable membrane is preferably 200 to 1500 μm.

The active ingredient impervious component of the membrane is water insoluble, but occasionally water permeable.
Minor constituents of the membrane that allow the active ingredient to exit will dissolve in water resulting in the generation of pores that allow the active ingredient and excipients to exit the core in an aqueous environment It may be a water-soluble material.

  Alternatively, the minor component of the membrane that allows the active ingredient to exit may be permeable to each of water, active ingredient and related excipients. The minor component of the membrane may also be porous.

  Further, the active ingredient permeable component, when present, may exhibit pH-dependent solubility or porosity such that the permeability of the membrane to the active ingredient varies with pH in an aqueous environment.

The active ingredient permeable component, when present, may exhibit solubility or porosity independent of pH.
Preferred materials for the active ingredient impervious component of the membrane are ethyl cellulose, polyvinyl chloride, methyl cellulose, polyurethane, cellulose acetate, polycarbonate, EUDRAGIT RS (EUDRAGIT RS is a trademark) and shellac.

  Preferred materials for the active ingredient permeable component of the membrane that are pH dependent are cellulose acetate phthalate, polyvinyl acetate phthalate, EUDRAGIT L (EUDRAGIT L is a trademark), EUDRAGIT S (EUDRAGIT S is a trademark), methylcellulose phthalate, hydroxyethylcellulose phthalate and hydroxypropylmethylcellulose phthalate.

  Preferred materials for the active ingredient permeable component of the membrane that are not pH dependent are polyvinyl alcohol, polyvinylpyrrolidone, EUDRAGIT RL (EUDRAGIT RL is a trademark), fumaric acid, citric acid, tartaric acid, citric acid Sodium sulfate, sodium bicarbonate, sodium fumarate, sodium carbonate, monosaccharides and disaccharides, hydroxypropylmethylcellulose, polyethylene glycol and propylene glycol.

A particularly suitable monosaccharide is glucose.
Eudragit polymers are polymeric lacquer materials based on acrylates and / or methacrylates that change permeability.

  More particularly, Eudragit polymers are polymeric lacquer materials based on acrylates and / or methacrylates. EUDRAGIT RS and RL are acrylic resins that include copolymers of acrylic acid and methacrylic acid esters having a low content of quaternary ammonium groups, and are available from Röss Pharma GmbH (Messrs. Rohm Pharma GmbH). It is described in the pamphlet “EUDRAGIT” (1986). Eudragit RL and RS are freely permeable (RL) or slightly permeable (RS), respectively, independent of pH. EUDRAGIT L and S are described in the same pamphlet and have pH-dependent permeability.

  The unique permeable membrane preferably comprises the selected active ingredient in a suitable manner in each suitable solvent together with at least one active ingredient permeable component and at least one active ingredient impermeable component. Formed by dissolving at a concentration that allows it to be sprayed using an air spray or an airless spray system. Preferably, the active ingredient is chlorpheniramine maleate, dextromethorphan hydrobromide and noscapine hydrochloride at a concentration of about 10% of the total concentration of active ingredient per tablet. Preferably, the working concentration of each membrane component varies between 0.5% and 7.5%, depending on the materials involved and the viscosity of the resulting solution.

  Each solution of film constituents may contain one or more additives such as plasticizers or other additives such as colorants and opacifiers that facilitate spraying. However, these additives do not substantially affect the properties of the film that is formed. The final solution used in coating the tablet core is a solution of soluble / permeable components and a solution of insoluble / impermeable components, preferably in a ratio of soluble to insoluble components of 1: 8. And 8: 1. Pigments, plasticizers, colorants and other conventional additives may also be added to the final solution.

  Preferably, the membrane is formed around the tablet core by spraying using an air spray system or an airless spray system and standard tablet coating equipment. As noted above, the unique permeable membrane preferably has a thickness of 200-1500 μm, corresponding to a 2-15% weight increase per tablet. After spraying, the coated tablets are oven dried at 104-122 ° F. (40-50 ° C.) for about 8 hours.

  Tablets coated with a film have a dissolution rate determined by the solubility of the active ingredients and excipients in the core tablet and the film composition. As already indicated, in order to achieve a rapid onset of action of the active ingredient, it is preferable to have an amount that serves for immediate release of at least one active ingredient.

The invention is further illustrated by the following examples.
Example 1
With the exception of Aerosil 200 (Aerosil is a trademark) and magnesium stearate, all of the tablet ingredients were passed through a hammer mill fitted with a 20 mesh sieve.

  Compressible sugar (3.616 kg), potassium chloride (1.607 kg) and chlorpheniramine maleate (0.58 kg) were placed in a crossflow blender and blended together for 10 minutes. To this formulation was added phenylpropanolamine hydrochloride (0.36 kg), dextromethorphan hydrobromide (0.434 kg), noscapine hydrochloride (0.434 kg) and Aerosil 200 (Aerosil 200) (0.018 kg). ) And the entire mixture was blended for an additional 20 minutes. Magnesium stearate (0.037 kg) and stearic acid (0.074 kg) were then added and blended with the other ingredients for 5 minutes.

  The formulation was compressed on a rotary tablet press fitted with a standard standard concave oval punch with dimensions of 13 mm x 7 mm. The tablets were compressed at a weight of 436 mg / tablet.

  Uncoated tablet cores were coated with a solution containing the following three of the four active ingredients in the following amounts:

  The above-mentioned amount of the active ingredient was mixed in a solution comprising the following ingredients to obtain the coating solution.

SD3A is a trade name of industrial modified alcohol (methylated alcohol).
The film coating solution was applied to the tablet core using an Accela Cota (Accela Cota is a trademark) (10 ″ pan) coating apparatus. A 10% weight gain is achieved in the core. The film-coated tablets were subsequently oven dried at 104 ° -122 ° F. (40 ° -50 ° C.) for more than 8 hours. 90 kg) in a mixture of Dricklea (Drickleear is a trademark) (0.10 kg) Cosmetic coating and Chromatone (Chromatone is a trademark) (0.10 kg) pigment coating A coating was applied, both Drecleer and Chromatone were Manufactured by Crompton and Knowles Inc. When tested by the paddle method described in the United States Pharmacopeia XXI using water as the vehicle, the dissolution rates of each active ingredient are as shown in Table 1. Measured.

Example 2
With the exception of Aerosil 200 and magnesium stearate, all of the tablet ingredients were passed through a hammer mill fitted with a 20 mesh sieve.

  Compressible sugar (7.332 kg), potassium chloride (3.214 kg) and chlorpheniramine maleate (0.116 kg) were placed in a crossflow blender and blended together for 10 minutes. To this formulation was added phenylpropanolamine hydrochloride (1.46 kg), dextromethorphan hydrobromide (0.868 kg), noscapine hydrochloride (0.868 kg) and Aerosil 200 (0.036 kg). The entire mixture was blended for an additional 20 minutes. Magnesium stearate (0.074 kg) and stearic acid (0.148 kg) were then added and blended with the other ingredients for 5 minutes.

The formulation was compressed on a rotary tablet press fitted with a regular standard concave oval punch having dimensions of 13 mm x 7 mm. The tablets were compressed at a weight of 436 mg / tablet.
The following ingredients,

Three of the following amounts of the four active ingredients mixed in a solution consisting of:

An uncoated tablet core was coated with a solution containing
The membrane coating solution was applied to the tablet core using an accelerator coater (10 "pan) coating apparatus. The core was sprayed with the coating solution until a 10.5% weight gain was achieved. Membrane-coated tablets were oven dried at 104 ° -122 ° F. (40 ° -50 ° C.) for more than 8 hours, as a final step, driclere (0.20 kg) and chromatone (0) in purified water (1.80 kg). A cosmetic coating consisting of a mixture of 20 kg) was applied and when tested by the paddle method described in the US Pharmacopeia XXI using water as the medium, the dissolution rate of each active ingredient was measured as shown in Table 2. .

Example 3
With the exception of Aerosil 200 and magnesium stearate, all of the tablet ingredients were passed through a hammer mill fitted with a 20 mesh sieve.

  Compressible sugar (67.5 kg), potassium chloride (30.0 kg) and chlorpheniramine maleate (1.08 kg) were placed in a cross flow blender and blended together for 10 minutes. To this formulation was added phenylpropanolamine hydrochloride (13.5 kg), dextromethorphan hydrobromide (8.1 kg), noscapine hydrochloride (8.1 kg) and Aerosil 200 (0.33 kg). The entire mixture was blended for an additional 20 minutes. Magnesium stearate (0.69 kg) and stearic acid (1.38 kg) were then added and blended with the other ingredients for 5 minutes.

The formulation was compressed on a rotary tablet press fitted with a regular standard concave oval punch having dimensions of 13 mm x 7 mm. The tablets were compressed at a weight of 436 mg / tablet.
The following ingredients,

Three of the following amounts of the four active ingredients mixed in a solution consisting of:

An uncoated tablet core was coated with a solution containing
The membrane coating solution was applied to the tablet core using an accelerator coater (48 "pan) coating apparatus. The core was sprayed with the coating solution until a 9% weight gain was achieved. The tablets were oven-dried at 104 ° -122 ° F. (40 ° -50 ° C.) for more than 8 hours, as a final step, Drecleer (1.85 kg) in purified water (16.65 kg) and A cosmetic coating consisting of a mixture of chromatones (1.85 kg) was applied, when tested by the paddle method described in US Pharmacopeia XXI using water as the medium, the dissolution rate of each active ingredient as shown in Table 2. Measured.

Example 4
Uncoated tablets were prepared as outlined in Example 3.
The tablet cores were coated in an accelerator coater fitted with a 48 ″ pan until a weight gain of 11.25% was obtained. The coating solution composition used was similar to that outlined in Example 3. It was.

  After oven drying and applying the cosmetic coating, the tablets produced the following dissolution rates when tested by the paddle method described in US Pharmacopeia XXI using water as the vehicle. The dissolution rate of each active ingredient was measured as shown in Table 4.

  In the case of the illustrated tablet, the rate-controlled membrane coating allows water to enter the solution and drug out of the tablet at the desired rate. A small amount of the indicated drug is released quickly for immediate action, while a slower uniform release across the entire surface of the tablet provides effective relief from normal cold symptoms for up to 12 hours. One tablet according to the present invention taken twice a day provides unaltered relief from normal cold symptoms throughout the day and facilitates a restful night's sleep, thereby reducing common cold discomfort and Relieve symptoms.

  The present invention is not limited to the embodiments described above and can be improved and / or varied without departing from the scope of the invention.

Claims (14)

  A tablet core containing a number of active ingredients together with a pharmaceutically acceptable excipient, and a unique permeable membrane surrounding the core and containing at least one active ingredient present in the core And the membrane contains a large amount of components that are impermeable to each active ingredient and each active ingredient present in the core and pharmaceutically acceptable loading when the tablet is placed in an aqueous environment. Cough / cold tablet formulation with controlled release and absorption, characterized in that the dosage forms contain small amounts of components that allow them to exit at a rate that allows their controlled release and absorption. .   A unique permeable membrane includes a water-soluble component that is permeable to each active ingredient and a water-insoluble component that is impermeable to each active ingredient, the water-soluble component being a tablet When placed in an aqueous environment, it dissolves and leaves each active ingredient and pharmaceutically acceptable excipient present in the core at a rate that allows controlled release and absorption. A controlled cough / cold tablet formulation with controlled release and absorption as claimed in claim 1, which results in the generation of pores that allow   3. The controlled release and absorption tablet preparation for cough / cold according to claim 1 or 2, wherein the components of the tablet core contain an antihistamine, a decongestant and a cough suppressant.   4. The controlled release and absorption cough / cold tablet formulation according to claim 3, wherein the tablet core comprises an antihistamine, a decongestant and two cough suppressants.   Controlled release and absorption according to claim 4, characterized in that the tablet core contains chlorpheniramine maleate, phenylpropanolamine hydrochloride, dextromethorphan hydrobromide and noscapine hydrochloride. Tablet preparation for cold / cold.   That chlorpheniramine maleate, phenylpropanolamine hydrochloride, dextromethorphan hydrobromide and noscapine hydrochloride are present in a weight ratio of about 0.1: 1: 0.7: 0.7. 6. Cough / cold tablet formulation with controlled release and absorption according to claim 5.   7. Release and absorption according to any one of claims 1 to 6, characterized in that the tablet core contains one or more highly soluble components that cause a liquid flow from the core in an aqueous environment. Controlled cough / cold tablet formulation.   A highly soluble ingredient is represented by a number of active ingredients or each active ingredient itself, potassium chloride, sodium bicarbonate, sodium citrate, sodium carbonate, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid or mixtures thereof. A controlled release and absorption cough / cold tablet formulation according to claim 7, characterized in that The release rate of each active ingredient is a rate that does not irritate the gastric mucosa, and when the rate is measured according to the paddle method described in the US Pharmacopoeia XXI in water, the following dissolution distribution:
(A) 15-40% of each active ingredient is released in the measurement after 1.5 hours,
(B) 35 to 65% of each active ingredient is released in the measurement after 3 hours, and (c) 75% or more of each active ingredient is released in the measurement after 6 hours. 9. The controlled release and absorption cough / cold tablet formulation according to any one of claims 1 to 8, characterized in that it is measured in vitro as a substantially corresponding dissolution rate.   10. The unique permeable membrane contains at least one active ingredient for immediate release of the active ingredient for rapid onset of action following tablet administration. Cough / cold tablet formulation with controlled release and absorption according to any one of the preceding claims.   11. Release and absorption according to claim 10, characterized in that the concentration of multiple active ingredients or each active ingredient in a unique permeable membrane is about 10% of the total amount of each active ingredient in the tablet. Controlled cough / cold tablet formulation.   The active ingredient impervious component of the membrane is ethyl cellulose, polyvinyl chloride, methyl cellulose, polyurethane, cellulose acetate, polycarbonate, shellac or acrylate, which is slightly permeable to many active ingredients or to each active ingredient and water 12. A controlled release and absorption cough / cold tablet formulation according to any one of the preceding claims, wherein the tablet formulation is selected from copolymers of methacrylic acid esters and methacrylates.   Cellulose acetate phthalate, polyvinyl acetate phthalate, methylcellulose, which has an active ingredient permeable constituent, exhibits pH-dependent solubility or porosity, and is freely permeable to many active ingredients or to each active ingredient and water 13. Controlled release and absorption cough according to any one of the preceding claims, selected from phthalates, hydroxyethylcellulose phthalates, hydroxypropylmethylcellulose phthalates, or copolymers of acrylic and methacrylic esters. / Tablet preparation for colds.   Active ingredient permeable constituents exhibit solubility or porosity independent of pH, and are freely permeable to many active ingredients or to each active ingredient and water, polyvinyl alcohol, polyvinyl pyrrolidone, fumaric acid, Citric acid, tartaric acid, sodium citrate, sodium bicarbonate, sodium fumarate, sodium carbonate, monosaccharide, disaccharide, hydroxypropylmethylcellulose, polyethylene glycol, propylene glycol or copolymers of acrylic acid ester and methacrylic acid ester 13. A controlled cough / cold tablet formulation with controlled release and absorption as claimed in any one of the preceding claims.