CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION

Abstract: A solid, controlled release, pharmaceutical composition comprising a drug and an anionic surfactant, incorporated in a matrix comprising a hydrophilic polymer, wherein the drug is either an acid addition salt of an organic base or a quaternary ammonium salt, provided that, the organic base is not propranolol or chlorpheniramine. Preferably the drug is an acid addition salt of an organic amine, the surfactant is a sulphosuccinate and the polymer is a water-soluble hydroxyalkyl cellulose ether.

Description: The present invention relates to a solid, controlled release, pharmaceutical composition and, in particular, to a composition containing a drug, a hydrophilic polymer and an anionic surfactant. The use of hydrophilic polymers in the controlled release of medicaments is known. A problem with such polymers is, however, that large quantities of the hydrophilic material is often required in order to effect proper control of drug release. This is a particularly severe problem when the unit dose of the medicament is large (above about 60% by wt). The use of anionic surfactants in solid pharmaceutical compositions is also known. Until recently, however, the presence of such surfactants was designed to facilitate fast and total release of the medicament from the composition (see, for example, Japanese Kokai 7320778 and A.A. Kassem et al ., J.Drug. Research , 1974, 6, 95). EP-A-0157695, published on 9 October 1985, describes a controlled release composition containing a drug, a water soluble, nonionic cellulose ether and an anionic surfactant. The active ingredient of EP-A-0157695 can be any type of medicament which acts locally, systemically, transbuccally or rectally. EP-A-0157695, however, does not describe the particular advantages obtained, in terms of drug release, when the drug is either the acid addition salt of an organic base or a quaternary ammonium salt. P.B. Daly et al ., Int.J.Pharm. , 1984, 18 , 201 also describes a controlled release composition containing a drug (chlorpheniramine maleate), a cellulose ether and an anionic surfactant. Once again, however the particular advantages accruing from such a system, when the drug is cationic entity (i.e. an acid addition salt or an organic base or a quaternary ammonium salt), are not identified. According to the present invention, therefore, there is provided a solid, controlled release, pharmaceutical composition comprising a drug and an anionic surfactant incorporated in a matrix comprising a hydrophilic polymer wherein the drug is either an acid addition salt of an organic base or a quaternary ammonium salt, provided that the organic base is not propranolol or chlorpheniramine; the rate of drug release from the composition being independent of pH between pH 1.5 and 7.0. Preferably the composition is in unit dosage form and administered by the oral route, especially as a tablet or as a capsule containing solid granules. The present inventors have found that, when the drug is an acid addition salt of an organic base or a quaternary ammonium salt, the anionic surfactant exercises an enhanced level of control over drug release. It appears that this enhanced effect is achieved by complex formation between the acid addition salt (of the organic base) or the quaternary ammonium salt and the anionic surfactant, the complex formed being water soluble at all biological pHs, especially between pH 1.5 to 7.0. In a particularly preferred embodiment of the present composition a substantial proportion [more that 70% (by wt), especially more than 90% (by wt)] of the drug in the composition is present in the form of the complex formed between the drug and the anionic surfactant. The combined use of the hydrophilic polymer and the anionic surfactant allows considerable flexibility in the control of drug release from compositions according to this invention. The rate of drug release, which is independent of pH, may be altered simply by modifying the polymer/surfactant ratio. Thus, by varying the ratio of the polymer to the surfactant in the composition, the release of a drug at any point within the digestive tract (and at any pH within the tract, 1.5 to 7.0) may be controlled. Furthermore, the use of the anionic surfactant, in combination with the hydrophilic polymer, allows the quantity of the polymer in the composition to be reduced without detriment to the control of drug release. This is particularly advantageous when the composition contains a large quantity of drug. The combination (polymer/surfactant) also facilitates the compression (and shaping) of the present pharmaceutical composition into unit dosage forms. The anionic surfactants which are effective in the present composition include alkali metal sulphates, such as sodium or potassium dodecylsulphate, sodium octadecylsulphate, and, which is preferred, alkali metal sulphonates, such as the alkali metal salts of benzene sulphonates, naphthalene sulphonates and, especially, dialkylsulphosuccinates. An alkali metal, especially sodium, salt of dioctylsulphosuccinate is particularly preferred as the anionic surfactant of the present composition. Remarkably, dioctyl sodium sulphosuccinate is not absorbed upon oral administration. The hydrophilic polymer may be any of the hydrophilic polymers employed in pharmaceutical compositions, especially controlled release pharmaceutical compositions. Examples include carboxyalkylcelluloses, alginic acid derivatives and carboxypolymethylenes (e.g. Carbopol, Trade Mark). Preferably, however, the hydrophilic polymer is a water soluble, non ionic cellulose ether, especially a hydroxyalkyl cellulose ether. Examples include hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and, which is preferred, hydroxypropylmethyl cellulose. Most preferably, the hydrophilic polymer, especially the cellulose ether, has a number average molecular weight of at least 50,000, especially at least 75,000. The amount of the hydrophilic polymer and the anionic surfactant in the present composition, as well as the ratio of these materials, will depend, inter alia , on the rate of drug release required. Preferably, the combined wt % of polymer and surfactant in the present composition is between 10% and 60%, especially between 10% and 50%. The preferred ratio (of polymer to surfactant) is between 50 to 1 and 1 to 2, especially between 30 to 1 and 1 to 1. Preferably each unit dose of the present composition contains between 1mg and 30mg, especially between 2mg and 20mg of the anionic surfactant. In the case of dioctyl sodium sulphosuccinate which at high levels acts as a laxative, the use of such low levels of the surfactant represents a distinct advantage. The drug may be either any acid addition salt (inorganic or organic) of an organic base or any quaternary ammonium salt. Preferably the drug is an acid addition salt of an organic amine. Examples of suitable drugs are: a) Analgesic agents; e.g. salts of morphine, codeine, ethyl morphine, dihydrocodeine, hydromorphone, phenazocine, pentazocine, buprenorphine, meptazinol, flupirtine, b) Antiinflammatory agents; e.g. salts of aminopyrine, c) Antihistamines; e.g. salts of clemastine, mepyramine, diphenylhydramine, dexchlorpheniramine, d) Topical anaesthetics; e.g. salts of lidocaine, procaine, e) Vasodilators; e.g. salts of papaverine, diltiazem, nicardipine, f) Antitussives and expectorants, e.g. salts of isoprotenerol, dextromethorphan, g) Antihypertensives; e.g. salts of clonidine, h) Antineoplastic agents; e.g. salts of doxorubicin, i) Bronchodilators; e.g. ipratropium bromide, and salts of albuterol (salbutamol), j) Antiarrythmic agents; e.g. salts of verapamil, quinidine, k) Antibiotics or Fungicides; e.g. salts of tetracyclines, neomycine, l) Chemotherapeutic agents; e.g. salts of clotrimazole, m) Oral antiseptics; e.g. dequalinium chloride, and salts of chlorhexidine, ethacridine, n) Anticholinergics; e.g. salts of scopolamine, o) Muscle Relaxants; e.g. salts of baclofen, cyclobenzaprine, p) Drugs for treatment of ulcers; e.g. salts of cimetidine, ranitidine, q) Antiemetics; e.g. salts of metoclopramide, r) Antimalarials; e.g. salts of quinine, s) Antipsychotics; e.g. salts of perphenazine, Particularly preferred drugs for use in the present composition are acid addition salts of metoclopramide, codeine, ethylmorphine, morphine, dextromethorphan, quinidine, quinine, dihydrocodeine, hydromorphone, perphenazine, diltiazem, meptazinol and flupirtine, especially metoclopramide hydrochloride, codeine phosphate, ethylmorphine hydrochloride, morphine sulphate, dextromethorphan hydrobromide, quinidine polygalacturonate, quinine sulphate, dihydrocodeine tartrate, hydromorphone hydrochloride, perphenazine hydrochloride, diltiazem hydrochloride, meptazinol hydrochloride and flupirtine maleate. These drugs can be used either singly or as a mixture of two or more. The amount of drug to be blended in a solid dosage unit will generally be enough to maintain a therapeutic level of the drug in the bloodstream for a predetermined period (preferably 8 hours or longer). In addition to the constituents discussed above, the present controlled release pharmaceutical composition may also contain certain of the known excipients, such as lubricants, binders, vehicles, colouring agents, taste controlling agents and odour controlling agents, that are employed to improve the appearance, odour or taste of pharmaceutical preparations. In order to facilitate the preparation of a unit dosage form from the present composition there is provided, in a further aspect of the present invention, a process for the preparation of a solid, controlled release, pharmaceutical unit dosage form comprising granulating a composition comprising a drug, a hydrophilic polymer and an anionic surfactant and, optionally, compressing and shaping the granules wherein the drug is either an acid addition salt of an organic base or a quaternary ammonium salt, provided that, the organic base is not propranolol or chlorpheniramine. In a particularly preferred embodiment of the present process, the anionic surfactant is dissolved in a C₁ - C₆ alkyl alcohol, especially a C₂-C₄ alkyl alcohol, or in an aqueous alcoholic solution and the hydrophilic polymer is then mixed with the surfactant solution to form a homogeneous mixture. Granulation of this mixture is followed by the addition of the drug to the granules. Controlled release pharmaceutical compositions according to the present invention, together with processes for their preparation will now be described by way of example only. Example 1 Dioctyl sodium sulphosuccinate (4.0gm) was dissolved in isopropanol (25ml). Hydroxypropylmethyl cellulose (90gm, Metolose 90SH 4000) was mixed with the sulphosuccinate solution until the mixture was homogeneous, the formation of granules being avoided. The mixture was then granulated and sieved through a 16 mesh screen. The granules were left to dry in the air until the isopropanol had evaporated. Quinidine polygalacturonate (288.75gm) and lactose (32.63gm) were then added and the whole was mixed thoroughly. Magnesium stearate (0.42gm) and talc (4.2gm) were then added and mixing was continued until a homogeneous mixture was obtained. Finally, the mixture was regranulated and sieved through a 16 mesh screen. The granules obtained were compressed and shaped into one thousand 420mg tablets, each containing 288.75mg of quinidine polygalacturonate. Example 2 The procedure of Example 1 was repeated except that the amounts of materials used were as follows: This produced 1,000 tablets weighing 580mg and containing 412.5mg of quinidine polygalacturonate. Example 3 Metoclopramide hydrochloride (15gm) was mixed with hydroxypropylmethyl cellulose (18gm) and lactose (80.75gm). The mixture was granulated with a solution of dioctyl sodium sulphosuccinate (7.5gm) in isopropanol. The granules were then dried and lubricated, with talc (2.5gm) and magnesium stearate (1.25gm). The granules obtained were compressed and shaped into 1000 tablets each weighing 125mg and each containing 15mg of metoclopramide hydrochloride. Example 4 The procedure of Example 3 was followed except that hydroxypropylmethyl cellulose (30gm) and dioctyl sodium sulphosuccinate (5gm) was used. The amount of lactose was reduced to 71.25gm. This produced 1000 tablets weighing 125mg and containing 15mg of metoclopramide hydrochloride. Example 5 (Comparative) Procedure of Example 3 was followed except that no dioctyl sodium sulphosuccinate was used and the amount of hydroxypropylmethyl cellulose was increased to 42gm. The amount of lactose was reduced to 64.25gm. Example 6 The procedure of Example 3 was repeated with the following ingredients, This produced 1000 tablets weighing 125mg and containing 15mg of metoclopramide hydrochloride. Examples 7-10 The procedure of Example 6 was followed except that the amount of dioctyl sodium sulphosuccinate was varied as follows: In each case, the amount of lactose was increased, as required, in order to give tablets the same weight as produced in Example 6. Example 11 (Comparative) The procedure of Example 6 was repeated except that no dioctyl sodium sulposuccinate was employed and the amount of lactose was increased by 12.5gm. EXAMPLE 12 The procedure of Example 1 was repeated with the following ingredients, This produced 1000 tablets weighing 125mg, each containing 30mg of morphine sulphate. Example 13 The procedure of Example 1 was repeated with the following ingredients, This produced 1000 tablets weighing 125mg, each containing 30mg of codeine phosphate. Examples 14 and 15 The procedure of Example 4 was followed except that the dioctyl sodium sulphosuccinate was replaced by sodium dodecylsulphate (Example 14) and sodium dodecylbenzene sulphonate (Example 15). Dissolution Studies The rate of release of various compositions according to this invention were investigated using the USP Paddle Method (Propharmacopoeia no. 79) at 50rpm in 500ml. on a pH gradient: pH 1.5 for the first hour, pH 4.5 for the second hour and pH 6.9 thereafter. The temperature was 37◊C, samples were taken every hour. Using this method, the dissolution rate of tablets prepared by Examples 3 to 11 above were determined. Results are given in the Tables below. Clinical Studies A comparative single dose pharmacokinetic study of two quinidine polygalacturonate preparations, namely quinidine polygalacturonate 412.5mg tablets prepared as described in Example 2 and controlled release quinidine polygalacturonate 412.5mg capsules (Cardioquine, Trade Mark) was carried out on 4 volunteers. Results are given in Table 5. A randomised, crossover, single dose comparative pharmacokinetic study of two quinidine polygalacturonate preparations, namely quinidine polygalacturonate 412.5mg tablets, prepared as described in Example 2, and controlled release quinidine polygalacturonate 412.5mg capsules (Cardioquine, Trade Mark), was carried out on 12 volunteers. Results are given in Tables 6, 7 and 8.

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A solid, controlled release pharmaceutical composition comprising a drug and an anionic surfactant, incorporated in a hydrophilic, polymer matrix, characterised in that the drug is either an acid addition salt of an organic base or a quaternary ammonium salt and further in that the rate of drug release from the composition is independent of pH between pH 1.5 and 7.0, provided that the organic base is not propranolol or chlorpheniramine. A composition according to claim 1 characterised in that the drug is an acid addition salt of an organic base, preferably the acid addition salt of an organic amine. A composition according to either claim 1 or claim 2, characterised in that the drug is selected from acid addition salts of metoclopramide, codeine, ethylmorphine, morphine, dextromethorphan, quinidine, quinine, dihydrocodeine, hydromorphone, perphenazine, diltiazem, meptazinol and flupirtine, especially metoclopramide hydrochloride, codeine phosphate, ethylmorphine hydrochloride, morphine sulphate, dextromethorphan hydrobromide, quinidine polygalacturonate, quinine sulphate, dihydrocodeine tartrate, hydromorphone hydrochloride, perphenazine hydrochloride, diltiazem hydrochloride, meptazinol hydrochloride and flupirtine maleate. A composition according to any one of claims 1 to 3 characterised in that the anionic surfactant comprises a sulphonate surfactant, especially a sulphosuccinate surfactant. A composition according to claim 4 characterised in that the anionic surfactant comprises a dialkyl sulphosuccinate surfactant, especially dioctyl sulphosuccinate, alkali metal salt. A composition according to any one of claims 1 to 5 characterised in that the hydrophilic, polymer matrix comprises a water soluble, nonionic cellulose ether, especially a hydroxyalkyl cellulose ether. A composition according to any one of claims 1 to 6 characterised in that the total weight of the hydrophilic, polymer matrix and the anionic surfactant in the composition is between 10% and 60%, especially between 10% and 50%. A composition according to any one of claims 1 to 7 characterised in that the composition is in the form of a unit dose and the unit dose contains between 1 and 30mg, preferably between 2 and 20mg, of the anionic surfactant. A process for the preparation of a solid, controlled release, pharmaceutical unit dosage form according to claim 1 comprising granulating a composition comprising a drug, a hydrophilic polymer and an anionic surfactant and, optionally, compressing and shaping the granules characterised in that the drug is either an acid addition salt of an organic base or a quaternary ammonium salt, provided that, the organic base is not propranolol or chlorpheniramine. A complex between an anionic surfactant and a drug which is either an acid addition salt of an organic base or a quaternary ammonium salt, provided that, the organic base is not propranolol or chlorpheniramine wherein the rate of drug release from the complex, when the complex is incorporated in a hydrophilic, polymer matrix, is controlled and independent of pH between pH 1.5 and 7.0. Claims for the following Contracting State : AT A process for the preparation of a solid, controlled release, pharmaceutical unit dosage form comprising forming a composition comprising a drug, a hydrophilic polymer and an anionic surfactant and, optionally, compressing and shaping the composition characterised in that the drug is either an acid addition salt of an organic base or a quaternary ammonium salt, provided that the organic base is not propranolol or chlorpheniramine, and that the rate of drug release from the composition is independent of pH between pH 1.5 and 7.0. A process according to claim 1 characterised in that the drug is an acid addition salt of an organic base, preferably the acid addition salt of an organic amine. A process according to either claim 1 or claim 3, characterised in that the drug is selected from acid addition salts of metoclopramide, codeine, ethylmorphine, morphine, dextromethorphan, quinidine, quinine, dihydrocodeine, hydromorphone, perphenazine, diltiazem, meptazinol and flupirtine, especially metoclopramide hydrochloride, codeine phosphate, ethylmorphine hydrochloride, morphine sulphate, dextromethorphan hydrobromide, quinidine polygalacturonate, quinine sulphate, dihydrocodeine tartrate, hydromophone hydrochloride, perphenazine hydrochloride, diltiazem hydrochloride, meptazinol hydrochloride and flupirtine maleate. A process according to any one of claims 1 to 3 characterised in that the anionic surfactant comprises a sulphonate surfactant, especially a sulphosuccinate surfactant. A process according to claim 4 characterised in that the anionic surfactant comprises a dialkyl sulphosuccinate surfactant, especially dioctyl sulphosuccinate, alkali metal salt. A process according to any one of claims 1 to 5 characterised in that the hydrophilic polymer comprises a water soluble, nonionic cellulose ether, especially a hydroxyalkyl cellulose ether. A process according to any one of claims 1 to 6 characterised in that the total weight of the hydrophilic polymer and the anionic surfactant in the composition is between 10% and 60%, especially between 10% and 50%. A process according to any one of claims 1 to 7 characterised in that the composition is in the form of a unit dose and the unit dose contains between 1 and 30 mg, preferably between 2 and 20 mg, of the anionic surfactant. A process for the preparation of solid controlled release, pharmaceutical unit dosage form comprising granulating a composition comprising a drug, a hydrophilic polymer and an anionic surfactant and, optionally, compressing and shaping the granules characterised in that the drug is either an acid addition salt of an organic base or a quaternary ammonium salt, provided that the organic base is not propranolol or chlorpheniramine, and that the rate of release from the composition is independent of pH between pH 1.5 and 7.0. A process for the preparation of a complex between an anionic surfactant and a drug comprising mixing the anionic surfactant and the drug to form the complex, characterised in that the drug is either an acid addition salt or an organic base or a quaternary ammonium salt, provided that, the organic base is not propranolol or chlorpheniramine and further characterised in that the complex, when incorporated in a hydrophilic matric, controls the rate of drug release, which rate is independent of pH between pH 1.5 and 7.0.

Inventors: DUMAS, JEANNE, LE HUEDE, ELISABETH, MARTANI, ROSA
Applicants: EUROCELTIQUE SA
Application year: 1986
Main classification: A61K9
IPC codes: A61K9