IE930370A1 - Differential release tablet with multiple active agents - Google Patents

Abstract

A controlled release and absorption cough/cold tablet formulation comprises a tablet core containing multiple active 5 ingredients, in particular an antihistamine, a decongestant and a cough suppressant, with a pharmaceutically acceptable excipient. A differentially permeable membrane surrounds the core and contains at least one of the active ingredients present in the core, the membrane including a major amount of a component which is impermeable to 10 each of the active ingredients and a minor amount of a component which, when the tablet is placed in an aqueous environment, permits the egress of each of the active ingredients and the pharmaceutically acceptable excipient present in the core, at a rate allowing controlled release and absorption thereof.

Description

This invention relates to controlled release pharmaceudcal1^ formulations and, in particular, to a controlled release cough/cold tablet formulation containing multiple active ingredients.

Multiple active ingredient formulations for use inter alia in the treatment of the common cold and influenza are known. Such formulations are a proven effective method of providing relief from symptoms such as nasal and sinus congestion, runny nose, sneezing, fever, minor sore throat, pain, body aches and hay fever or other respiratory allergies. Such formulations are conventionally immediate release formulations. Multiple active ingredient formulations, effective in alleviating the range of symptoms hereinbefore mentioned have not heretofore been available in a controlled release and absorption formulation.

Thus, Belgian Patent No. 900,824 discloses a controlled release tablet formulation for the release of potassium chloride through a differentially permeable membrane surrounding a tablet core; the potassium chloride representing about 66% by weight of the total tablet weight.

GB-A 2 218 905 discloses a controlled release tablet formulation for the release of potassium chloride through a differentially permeable membrane surrounding a tablet core; the potassium chloride component of the tablet being present in an amount of at least 80% weight of the tablet.

Single active ingredient controlled release tablet formulations are known wherein the active ingredient is released through a differentially permeable membrane surrounding a tablet core.

The term cough/cold as used herein is intended to embrace symptoms such as nasal and sinus congestion, runny nose, sneezing, fever, minor sore throat, pain, body aches and hay fever or other respiratory allergies.

It is an object of the present invention to provide an improved controlled release and absorption cough/cold tablet formulation containing multiple active ingredients from which the release of said active ingredients can be accurately controlled to ensure a predetermined rate of release and a more effective tablet formulation.

Accordingly, the invention provides a controlled release and absorption cough/cold tablet formulation, comprising a tablet core containing multiple active ingredients in association with a pharmaceutically acceptable excipient, and a differentially permeable membrane surrounding said core and containing at least one of tlie active ingredients present in the core, said membrane including a major amount of a component which is impermeable to each of the active ingredients and a minor amount of a component which, when the tablet is placed in an aqueous environment, permits the egress of each of the active ingredients and the pharmaceutically acceptable excipient present in the core at a rate allowing controlled release and absorption thereof.

In one embodiment, the differentially permeable membrane includes a water-soluble component which is permeable to each of the active ingredients and a water-insoluble component which is impermeable to each of the active ingredients, the water-soluble component dissolving when the tablet is placed in an aqueous environment resulting in a generation of of pores which permit the egress of each of the active ingredients and the pharmaceutically acceptable excipient present in the core at a rate allowing controlled release and absorption thereof.

Preferably, the ingredients of the tablet core include an antihistamine, a decongestant and a cough suppressant. Most especially, the tablet core contains an antihistamine, a decongestant and two cough suppressants.

In a preferred embodiment, the tablet core contains chlorpheniramine maleate, phenylpropanolamine HC1, dextromethorphan HBr and noscapine HC1.

Also, the tablet core can contain one or more highly soluble 5 ingredients to create a flow of liquid therefrom in an aqueous environment. The highly soluble ingredient can be the or each active ingredient per se, but also can suitably be potassium chloride, sodium bicarbonate, sodium citrate, sodium carbonate, citric acid, fumaric acid, malic acid, succinic acid or tartaric acid or a mixture thereof.

Chlorpheniramine maleate is an antihistamine, which helps to relieve sneezing, running nose and itching of the eyes, nose and throat. Drowsiness is less likely to be produced by chlorpheniramine than by many other antihistamines, and it is among the most suitable of its kind for daytime use.

Phenylpropanolamine HC1 is a decongestant, which facilitates free breathing by helping to relieve congestion of the nasal passages and sinuses. It is less likely to produce side effects associated with CNS stimulation than other drugs in the same class.

The use of the two cough-suppressant compounds dextromethorphan HBr and noscapine HC1, provide additive beneficial effects but avoid the side effects associated with an increased dose of either compound. They are incorporated to relieve dry, persistent, nonproductive coughs and with the intention of bringing the cough reflex under voluntary control. Dextromethorphan HBr and Noscapine HC1 both act centrally, do not produce euphoria or drowsiness, and are unlikely to cause dependence.

The combination of the aforementioned four active ingredients in a single dosage form from which release and absorption is controlled, provides a most effective means of combating the symptoms associated with coughs and colds. A single controlled absorption tablet formulation designed to target the majority of the symptoms herein ΙΕ 930370 embraced by the term cough/cold provides an advantage over conventional immediate release cough/cold therapies and over controlled absorption combination therapies which do not contain all four ingredients.

Use of a membrane barrier to provide effective programmed control over the rate of release of the four active ingredients from a tablet core ensures that the size of dosage form is maintained at very acceptable limits to facilitate intake of the tablets.

The rate of release of each of the active ingredients is at a rate which does not irritate the gastric mucosa, said rate suitably being measured in vitro as a dissolution rate which when measured according to U.S. Pharmacopoeia XXI paddle method in water substantially corresponds to the following dissolution profile: (a) from 15 to 40% of each active ingredient is released after 1.5 hours of measurement; (b) from 35 to 65% of each active ingredient is released after 3 hours of measurement; and (c) not less than 75% of each active ingredient is released after 6 hours of measurement.

Preferably, the above formulation comprises four components: chlorpheniramine maleate, phenylpropanolamine HC1, dextromethorphan HBr, and noscapine HC1 in a ratio by weight of approximately 0.1:1:0.7:0.7.

A representative tablet has the following composition: Chlorpheniramine maleate 4mg Phenylpropanolamine HC1 45mg Dextromethorphan HBr 30mg Noscapine HC1 30mg It is desirable to have at least one, and preferably more than one, of the active ingredients in the membrane for immediate release of said active ingredient(s) for rapid on-set of action following administration of the tablet at a concentration of approximately 10% of the total active ingredient concentration per tablet.

Thus, according to a preferred embodiment of the present invention, a controlled release and absorption tablet formulation is provided comprising a tablet core containing the active ingredients chlorpheniramine maleate, phenylpropanolamine HC1, dextromethorphan HBr, and noscapine HC1, in association with a pharmaceutically acceptable excipient and wherein the differentially permeable membrane surrounding the core contains the active ingredients chlorpheniramine maleate, dextromethorphan HBr and noscapine HC1.

The tablet core is preferably produced using a dry blend, direct compression technique which yields a tablet core which is nonfriable and sufficiently hard to withstand the application of the differentially permeable membrane.

Preferably, hardness is at a minimum of 40 newtons and friability of < 1.0% by weight.

The differentially permeable membrane is preferably between 200 and 1500 pm in thickness.

The active ingredient impermeable component of the membrane is water-insoluble, but optionally water-permeable.

The minor component of the membrane which permits the egress of the active ingredient may be a water-soluble material which dissolves in water resulting in a generation of pores which permit the egress of the active ingredients and excipient(s) from the core in an aqueous environment.

,E 930370 Alternatively, the minor component of the membrane which permits the egress of the active ingredients may be permeable to each of the water, active ingredients and the associated excipient(s). Said minor component of the membrane may also be porous.

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

The active ingredient permeable component when present may 10 also exhibit pH independent solubility or porosity.

Preferred materials for the active ingredient impermeable component of the membrane are: ethylcellulose, polyvinyl chloride, methylcellulose, polyurethane, cellulose acetate, polycarbonate, EUDRAGIT RS (EUDRAGIT RS is a trade mark), and shellac.

Preferred materials for an active ingredient permeable component of the membrane which is pH dependent are: cellulose acetate phthalate, polyvinylacetate phthalate, EUDRAGIT L (EUDRAGIT L is a trade mark), EUDRAGIT S (EUDRAGIT S is a trade mark), methylcellulose phthalate, hydroxyethylcellulose phthalate and hydroxypropylmethylcellulose phthalate.

Preferred materials for an active ingredient permeable component of the membrane which is pH independent are: polyvinyl alcohol, polyvinylpyrrolidone, EUDRAGIT RL (EUDRAGIT RL is a trade mark), fumaric acid, citric acid, tartaric acid, sodium citrate, sodium bicarbonate, sodium fumarate, sodium carbonate, monosaccharides and disaccharides, hydroxypropylmethyl cellulose, polyethylene glycol and propylene glycol.

An especially suitable monosaccharide is glucose. ® 930370 EUDRAGIT polymers are polymeric lacquer substances based on acrylate and/or methacrylate of varying permeability.

More specifically, EUDRAGIT polymers are polymeric lacquer substances based on acrylates and/or methacrylates. EUDRAGIT RS and RL are acrylic resins comprising copolymers of acrylic and methacrylate acid esters with a low content of quaternary ammonium groups and are described in the EUDRAGIT brochure of Messrs. Rohm Pharma GmbH (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 brochure and have a permeability which is pH dependent.

The differentially permeable membrane is preferably formed by dissolving the selected active ingredient(s) with at least one active ingredient permeable component and at least one active ingredient impermeable component in a respectively suitable solvent at a concentration which allows spraying with an air spray or airless spray system in conventional manner. Preferably, the active ingredients are chlorpheniramine maleate, dextromethoiphan HBr, and noscapine HC1 at concentrations of approximately 10% of the total concentration of said active ingredient per tablet. Preferably, the concentration of each membrane component used varies between 0.5% and 7.5% depending on the material involved and the viscosity of the resulting solution.

Each solution of membrane component may include one or more additives which facilitates spraying such as plasticizers or other additives such as colouring agents and opacifiers. These additives, however, do not substantially affect the nature of the membrane formed. The final solution used in coating the tablet cores is made by mixing the solutions of soluble/permeable component(s) and insoluble/impermeable component(s) so that the proportion of soluble to insoluble component(s) is preferably between 1:8 and 8:1. Pigments, plasticizers, colouring agents 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 or an airless spray system and standard tablet coating equipment. As stated above, the differentially permeable membrane preferably has a thickness of 200-1500 pm which corresponds to a weight gain per tablet of 2-15%. After spraying, the coated tablets are oven dried for about 8 hours at 104°-122°F.

The membrane coated tablets have a dissolution rate which is determined by the solubility properties of the active ingredient(s) and excipient(s) in the core tablet and by the composition of the membrane.

As indicated, it is preferable to have an amount of at least one of the active ingredients available for immediate release in order to achieve rapid on-set of action of the active ingredient.

The invention will be further illustrated by the following Examples.

Example 1 All tablet ingredients, with the exception of the Aerosil 200 (Aerosil is a trade mark) and magnesium stearate were passed through a hammermill fitted with a 20 mesh screen.

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. Phenylpropanolamine HC1 (0.36 kg), dextromethorphan HBr (0.434 kg), noscapine HC1 (0.434 kg), and Aerosil 200 (0.018 kg) were added to this blend, and the total mixture was further blended for 20 minutes. Magnesium stearate (0.037 kg) and stearic acid (0.074 kg) were then added and blended with the other ingredients for five minutes.

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

The uncoated tablet cores were coated with a solution containing the following amounts of three of the four active ingredients.

Chlorpheniramine maleate 0.006 kg Noscapine HC1 0.048 kg Dextromethorphan HBr 0.048 kg mixed into a solution consisting of the following ingredients: Ethylcellulose (7 cps) 0.241 kg Kollidon 30 (Kollidon 30 is trade mark) 0.096 kg Propylene glycol 0.048 kg SD3A anhydrous 6.419 kg SD3A is a trade name for industrial methylated spirits.

The membrane coating solution was applied to the tablet cores using an Accela Cota (Accela Cota is a trade mark) (10 pan) coating equipment. The cores were sprayed with the coating solution until a 10% weight gain was achieved. The membrane coated tablets were subsequently oven dried for not less than 8 hours at 104°-122°F. As a final step, a coating consisting of a mixture of Driklear (Driklear is a trade mark) (0.10 kg) cosmetic coating and Chromatone (Chromatone is a trade mark) (0.10 kg) pigment coating in purified water (0.90 kg) was applied. Driklear and Chromatone are both manufactured by Crompton and Knowles. When tested by the paddle method of the U.S. Pharmacopoeia XXI using water as the medium, the dissolution rate of each of the active ingredients was measured, as shown in Table 1.

TABLE 1 Dissolution (%/hr) Active Ingredient 1.5 3 6 Phenylpropanolamine HC1 30.5 55.1 93.8 Dextromethorphan HBr 34.8 56.3 88.6 Chlorpheniramine maleate 35.8 58.3 86.6 Noscapine HC1 34.3 54.6 95.7 Specification range 15-40% 35-65% > 75% Example 2 All tablet ingredients, with the exception of the Aerosil 200 and magnesium stearate were passed through a hammermill fitted with a 20 mesh screen.

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. Phenylpropanolamine HC1 (1.46 kg), dextromethorphan HBr (0.868 kg), noscapine HC1 (0.868 kg), and Aerosil 200 (0.036 kg) were added to this blend, and the total mixture was further blended for 20 minutes. Magnesium stearate (0.074 kg) and stearic acid (0.148 kg) were then added and blended with the other ingredients for five minutes.

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

The uncoated tablet cores were coated with a solution containing 20 the following amounts of three of the four active ingredients.

Chlorpheniramine maleate Noscapine HC1 Dextromethorphan HBr 0.012 kg 0.096 kg 0.096 kg mixed into a solution consisting of the following ingredients: Ethylcellulose (7 cps) 0.482 kg Kollidon 30 0.192 kg Propylene glycol 0.096 kg SD3A anhydrous 12.838 kg The membrane coating solution was applied to the tablet cores using an Accela Cota (10 pan) coating equipment. The cores were sprayed with the coating solution until a 10.5% weight gain was achieved. The membrane coated tablets were subsequently oven dried for not less than 8 hours at 104°-122°F. As a final step, a cosmetic coating consisting of a mixture of Driklear (0.20 kg) and Chromatone (0.20 kg) in purified water (1.80 kg) was applied. When tested by die paddle method of the U.S. Pharmacopoeia XXI using water as the medium, the dissolution rate of each of the active ingredients was measured, as shown in Table 2.

TABLE 2 Dissolution (%/hr) Active Ingredient 1.5 3 6 Phenylpropanolamine HC1 24.3 60.3 96.8 Dextromethorphan HBr 31.8 57.0 92.6 Chlorpheniramine maleate 32.6 61.5 101.7 Noscapine HC1 25.8 53.9 95.2 Specification range 15-40% 35-65% >75% Example 3 All tablet ingredients, with the exception of the Aerosil 200 and magnesium stearate were passed through a hammermill fitted with a 20 mesh screen.

Compressible sugar (67.5 kg), potassium chloride (30.0 kg) and chlorpheniramine maleate (1.08 kg) were placed in a crossflow blender and blended together for 10 minutes. Phenylpropanolamine HC1 (13.5 kg), dextromethorphan HBr (8.1 kg), noscapine HC1 (8.1 kg), and Aerosil 200 (0.33 kg) were added to this blend, and the total mixture was further blended for 20 minutes. Magnesium stearate (0.69 kg) and stearic acid (1.38 kg) were then added and blended with the other ingredients for five minutes.

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

The uncoated tablet cores were coated with a solution containing the following amounts of three of the four active ingredients.

Chlorpheniramine maleate 0.012 kg Noscapine HC1 0.900 kg Dextromethorphan HBr 0.900 kg mixed into a solution consisting of the following ingredients: Ethylcellulose (7 cps) 4.80 kg Kollidon 30 1.92 kg Propylene glycol 0.96 kg SD3A anhydrous 128.38 kg The membrane coating solution was applied to the tablet cores using an Accela Cota (48 pan) coating equipment. The cores were sprayed with the coating solution until a 9% weight gain was achieved. The membrane coated tablets were subsequently oven dried for not less than 8 hours at 104°-122°F. As a final step, a cosmetic coating consisting of a mixture of Driklear (1.85 kg) and Chromatone (1.85 kg) in purified water (16.65 kg) was applied. When tested by the paddle method of the U.S. Pharmacopoeia XXI using water as the medium, the dissolution rate of each of the active ingredients was measured, as shown in Table 3.

TABLE 3 Dissolution (%/hr) Active Ingredient 1.5 3 6 Phenylpropanolamine IIC1 32.3 61.1 97.8 Dextromethorphan HBr 36.9 62.3 99.4 Chlorpheniramine maleate 36.6 60.9 95.2 Noscapine HC1 38.3 58.5 88.7 Specification range 15-40% 35-65% >75% Example 4 Uncoated tablets were manufactured as outlined in Example 3.

The tablet cores were coated in an Accela Cota equipped with a 48 pan with a weight gain of 11.25%. The coating solution composition used was equivalent to that outlined in Example 3.

After oven drying and the application of the cosmetic coating, 10 the tablets generated the following dissolution rates when tested by the paddle method of the U.S. Pharmacopoeia XXI using water as the medium, the dissolution rate of each of the active ingredients was measured, as shown in Table 4.

TABLE 4 Dissolution (%/hr) Active Ingredient 1.5 3 6 Phenylpropanolamine 11C1 18.7 39.6 82.4 Dextromethorphan HBr 19.1 40.7 86.5 Chlorpheniramine maleate 21.3 42.6 89.5 Noscapine HC1 17.9 41.1 90.7 Specification range 15-40% 35-65% > 75% In the case in the exemplified tablets, the rate-controlling membrane coating allows entry of water and egress of drugs in solution from the tablet at the desired rate. A small amount of the indicated drugs is released quickly for immediate action, while slower uniform release over the entire surface of the tablet provides for effective relief from the symptoms of the common cold for up to twelve hours. One tablet in accordance with the invention taken twice daily provides consistent relief from the symptoms of the common cold throughout the day and facilitates a restful nights sleep, thereby, alleviating the discomfort and symptoms of the common cold.

The invention is not limited to the embodiments described above which may be modified and/or varied without departing from the scope of the invention.

Claims (13)

1. A controlled release and absorption cough/cold tablet formulation, comprising a tablet core containing multiple active ingredients in association with a pharmaceutically acceptable excipient, 5 and a differentially permeable membrane surrounding said core and containing at least one of the active ingredients present in the core, said membrane including a major amount of a component which is impermeable to each of the active ingredients and a minor amount of a component which, when the tablet is placed in an aqueous environment, 10 permits the egress of each of the active ingredients and the pharmaceutically acceptable excipient present in the core at a rate allowing controlled release and absorption thereof.

2. A formulation according to Claim 1, wherein the differentially permeable membrane includes a water-soluble component 15 which is permeable to each of the active ingredients and a waterinsoluble component which is impermeable to each of the active ingredients, the water-soluble component dissolving when the tablet is placed in an aqueous environment resulting in a generation of of pores which permit the egress of each of the active ingredients and the 20 pharmaceutically acceptable excipient present in the core at a rate allowing controlled release and absorption thereof.

3. A formulation according to Claim 1 or 2, wherein the ingredients of the tablet core include an antihistamine, a decongestant and a cough suppressant. 25

4. A formulation according to Claim 3, wherein the tablet core contains an antihistamine, a decongestant and two cough suppressants.

5. A fonnulation according to Claim 4, wherein the tablet core contains chlorpheniramine maleate, phenylpropanolamine HC1, 30 dextromethorphan HBr and noscapine HC1.

6. A formulation according to Claim 5, wherein the chlorpheniramine maleate, phenylpropanolamine HC1, dextromethorphan HBr and noscapine HC1 are present in a ratio by weight of approximately 0.1:1:0.

7. :0.7. 5 7. A formulation according to any preceding claim, wherein the tablet core contains one or more highly soluble ingredients to create a flow of liquid therefrom in an aqueous environment.

8. A formulation according to Claim 7, wherein the highly soluble ingredient is represented by the or each active ingredient per 10 se, potassium chloride, sodium bicarbonate, sodium citrate, sodium carbonate, citric acid, fumaric acid, malic acid, succinic acid or tartaric acid or a mixture thereof.

9. A formulation according to any preceding claim, wherein the rate of release of each of the active ingredients is at a rate which 15 does not irritate the gastric mucosa, said rate being measured in vitro as a dissolution rate which when measured according to U.S. Pharmacopoeia XXI paddle method in water substantially corresponds to the following dissolution profile: 20 (a) from 15 to 40% of each active ingredient is released after 1.5 hours of measurement; (b) from 35 to 65% of each active ingredient is released after 3 hours of measurement; and (c) not less than 75% of each active ingredient is released after 6 hours of measurement. 25 10. A formulation according to any preceding claim, wherein the differentially permeable membrane contains at least one of the active ingredients for immediate release of said active ingredient(s) for rapid on-set of action following administration of the tablet. 11. A formulation according to claim 10, wherein the concentration of the or each active ingredient in the differentially permeable membrane is at a concentration which is approximately 10% of the total of each said active ingredient in the tablet. 5 12. A formulation according to any preceding claim, wherein the active ingredient impermeable component of the membrane is selected from ethylcellulose, polyvinyl chloride, methylcellulose, polyurethane, cellulose acetate, polycarbonate, shellac or a copolymer of acrylic and methacrylic acid esters which is slightly permeable to the

10. Or each active ingredient and water.

11. 13. A formulation according to any preceding claim, wherein the active ingredient permeable component exhibits pH dependent solubility or porosity and is selected from cellulose acetate phthalate, polyvinylacetate phthalate, methylcellulose phthalate, 15 hydroxyethylcellulose phthalate, hydroxypropylmethylcellulose phthalate or a copolymer of acrylic and methacrylic acid esters which is freely permeable to the or each active ingredient and water.

12. 14. A formulation according to any one of Claims 1-12, wherein the active ingredient permeable component exhibits pH 20 independent solubility or porosity and is selected from polyvinyl alcohol, polyvinylpyrrolidone, fumaric acid, citric acid, tartaric acid, sodium citrate, sodium bicarbonate, sodium fumarate, sodium carbonate, monosaccharides, disaccharides, hydroxypropylmethyl cellulose, polyethylene glycol, propylene glycol or a copolymer of 25 acrylic and methacrylic acid esters which is freely permeable to the or each active ingredient and water.

13. 15. A formulation according to Claim 1, substantially as hereinbefore described with particular reference to the accompanying Examples.