Buoyant controlled release powder formulation

Abstract: A buoyant controlled release pharmaceutical powder formulation is provided which may be filled into capsules and releases a pharmaceutical of a basic character at a controlled rate regardless of the pH of the environment, which formulation includes a basic pharmaceutical, up to about 45% by weight of a pH dependent polymer which is a salt of alginic acid, such as sodium alginate, up to about 35% by weight of a pH-independent hydrocarbon gelling agent having a viscosity of up to about 100,000 centipoises in 2% solution at 20°C and excipients.

Description: The present invention relates to buoyant controlled release powder formulation ions. GB Patent Specification 2163648 suggests use of alginic acid as a hydrophilic gel forming substance in a slow release pharmaceutical preparation also containing a fat/oil which is solid at room temperature and having a specific gravity of not more than 1.0. The patent suggests the use of a hydrocolloid or alginic acid (among others) as the substance which forms a gel in water. PCT Patent Specification WO85/04806 discloses a low-sodium antacid composition useful in the treatment of reflux oesophagitis prepared from magnesium alginate and an effective acid-neutralizing amount of an antacid. The composition forms a foam or raft which floats on the stomach contents and is meant to precede the stomach contents into the oesophagus when reflux occurs and helps to protect the mucosa from further irritation. French Patent Specification 2636532 describes a pharmaceutical composition for use in treating gastric disorders comprising ranitidine or a salt thereof, alginic acid or a salt thereof and a carbonate or bicarbonate. The composition is limited to gastrointestinal disorders and moreover requires a carbon dioxide generating constituent for flotation. French Patent Specification 2512676 describes a controlled release composition floatable in gastric juices containing L-Dopa and a decarboxylase inhibitor as active ingredients incorporating a hydrocolloid and a fatty material. Upon oral ingestion, the capsule shell or tablet dissolves and the formulation comes in contact with gastric fluid causing hydration and increase in bulk volume and buoyancy. As the hydrate layer dissolves, new hydrate layers are formed and concurrently, the active ingredients are released until all medicaments are leached out and the remaining matrix, which is still buoyant is slowly dispersed or eliminated. The present invention provides a buoyant controlled release pharmaceutical formulation in the form of a capsule containing a powder, from which a pharmaceutical of a basic character is released at a controlled rate irrespective of the pH of the environment, the formulation comprising a pharmaceutical of a basic character, a pH-dependent polymer which is a salt of a polyuronic acid, and which is present in an amount not exceeding 45% by weight of the formulation; a pH-independent hydrocolloid gelling agent having a viscosity of from 50 to 100,000 mPas (centipoises) in 2% solution at 20°C, and which is present in an amount not exceeding 35% by weight of the formulation, said formulation being free of calcium ion and carbon dioxide-producing material and will float in gastric juices. The controlled release pharmaceutical formulation may thus be provided in a form which has prolonged drug release equivalent to a tablet of similar composition, pH independence of release rate equivalent to a tablet of similar composition, and yet has floating or buoyancy properties. This is especially surprising inasmuch as until now it was not thought possible that loose powder filled capsules could perform in the same way as granulated material that had undergone compression to form tablets (as disclosed in Howard et al., U. S. Patent No. 4,792,452), and also be buoyant so that it will float on gastric juices and thereby improve drug availability. Features of the preferred forms of the invention will now be described. Certain preferred features of the invention are also set out in the dependent claims. The buoyant controlled release powder formulation of the invention will release a pharmaceutical of a basic character at a controlled rate relatively independent of the pH of the environment such that in vivo consistent release is achieved throughout the gastrointestinal tract and will have buoyant properties so that it will have extended residence time in the stomach. This is achieved without gas generation in situ , or by the incorporation of fats or waxy solids into the matrix. Dissolution properties are also maintained essentially independent of pH without the need for calcium to effect gelation. The controlled release pharmaceutical formulation of the invention will be in the form of a powder (e.g. having an average particle size of within the range of from about 25 to about 1000 microns, preferably from about 50 to about 400 microns, and a bulk density of within the range of from about 0.1 to about 0.8 g/cm 3 , and preferably from about 0.15 to about 0.55 g/cm 3 ), which is filled into a capsule and includes a pharmaceutical of a basic character; a pH-dependent polymer which is a water soluble salt of a polyuronic acid, preferably alginic acid, in an amount not exceeding 45% by weight depending upon the nature of the pharmaceutical present, preferably from 15 to 45% by weight and more preferably from 20 to 35% by weight of the formulation; a pH-independent hydrocolloid gelling agent having a viscosity within the range of from 15 to 100,000 centipoises (mPas) and preferably from 50 to 15,000 centipoises in 2% solution at 20°C, in an amount not exceeding 35% by weight, preferably within the range of from 5 to 20% by weight and more preferably from 8 to 17% by weight of the formulation; and normally excipients and other conventional powder ingredients. The powder formulation of the invention will not contain calcium ions so there will be no calcium ions available to interact with the polyuronic acid salts. Additionally there will be no gas generation or incorporation of lipid materials to bring about buoyancy. It is theorized that upon oral ingestion of the sustained release buoyant powder-filled capsules of the invention, in an acid aqueous environment, such as the stomach, water penetrates the capsule shell initiating surface hydration of the pH-independent hydrocolloid gelling agent to form a gel layer and trapping air within the less dense powder bulk to account for the buoyant behavior of the capsule. At this low pH environment alginic acid is formed from the alginate salt and this modifies the gel layer. Erosion of the gel layer gradually exposes more dry matrix that hydrates to replenish the gel layer. Drug dissolves in the gel layer and diffuses out into the surrounding aqueous environment. Some interaction between the basic drug and the polyuronic acid may also be involved. After buoyancy is lost the dosage form is emptied from the stomach and changes in pH are encountered. During passage of the drug, contained in the form of a gelled powder plug, from the stomach down the digestive tract, the pH increases, using alginic acid as an example, this causes conversion of the acid form in the stomach to a more soluble salt. The gelling agent will then be less structured and more fluid in nature. Drug can diffuse more readily through the gel layer now and the ensuing increase in release rate from the matrix compensates for the reducing driving force for dissolution at the elevated pH values, where solubility of a basic drug is lower. The controlled release powder formulation of the invention does not contain calcium ions, or sodium bicarbonate or other carbon dioxide-producing material but it still will float in the stomach for an extended period. The pharmaceutical of a basic character will be present in the formulation of the invention in an amount not exceeding 75% by weight and preferably not exceeding 60% by weight. A wide variety of medicaments (of basic nature) which are orally administered in tablet form can be used in the form of a powder prepared according to this invention. These include, for example, adrenergic agents such as salts of ephedrine, desoxyephedrine, phenylephrine, epinephrine, albuterol, fenoterol, terbutaline and the like, cholinergic agents such as salts of physostigmine, neostigmine and the like, antispasmodic agents such as salts of atropine, methantheline, papaverine and the like, tranquilizers and muscle relaxants such as salts of fluphenazine, thioridazine, trifluoperazine, chlorpromazine, triflupromazine and the like, antidepressants like salts of amitriptyline, nortriptyline, and the like, other CNS acting drugs such as BMS 181101 BMY 14,802, buspirone, nefazadone, gepirone and tiospirone, antihistamines such as salts of diphenhydramine, chlorpheniramine, dimenhydrinate, tripelennamine, perphenazine, chlorprophenazine, chlorprophenpyridamine and the like, cardioactive agents such as salts of verapamil, diltiazem, gallapomil, cinnarizine, propranolol, metoprolol, sotalol, nadolol, and salts of any of the foregoing, antimalarials such as chloroquine and the like, analgesics such as propoxyphene, meperidine and the like, etc., sympathomimetics such as salts of phenylpropanolamine and pseudoephedrine. Other therapeutic agents having the same or different physiological activity can also be employed in pharmaceutical preparations within the scope of the present invention. The invention is particularly adapted for controlled release powder-filled capsules containing the calcium channel blocker verapamil (usually formulated in the form of its hydrochloride), and diltiazem or the beta-blocker metoprolol (usually formulated as the tartrate). The water soluble salts of polyuronic acids suitable for use herein includes water-soluble salts of alginic acids, for example, forms which are high in guluronic acid such as sourced from Laminaria Digitata, forms which are high in mannuronic acid such as sourced from Ascophyllum Nodosum, and mixed forms from algal sources, as well as water-soluble salts of pectic acid, that is polygalacturonic acid. The amount of a salt of a polyuronic acid that will be present will depend upon the pharmaceutical present and should not exceed 45% by weight of the powder formulation. Usually, the salt of the polyuronic acid will be present in an amount within the range of from 15 to 45% by weight and preferably from 20 to 40% by weight of the formulation. Such salt will preferably take the form of a salt of alginic acid, such as an alkali metal salt such as sodium alginate or potassium alginate or ammonium alginate, and preferably sodium alginate. The salt of alginic acid will have a viscosity of up to 500 or more centipoises in 1% solution at 25°C and preferably from 5 to 350 centipoises or from 4 to 300 centipoises. It will be appreciated that mixtures of the same or different alginic acid salts of the same or different viscosities may be employed herein. The polyuronic acid salt will be employed in a weight ratio to the hydrocolloid gelling agent of within the range of from 0.1:1 to 10:1 and preferably from 0.4:1 to 8:1. The hydrocolloid gelling agent, may be of the compressible or non-compressible type, and is essential to the practice of the invention in that it absorbs water, swells and forms a gelatinous layer. It will be of the type to provide a viscosity of 50 to 100,000 centipoises in a 2% aqueous solution at 20°C, and generally will have a molecular weight ranging from about 80,000 to about 300,000. Thus, the hydrocolloid is provided in an amount not exceeding 35% by weight of the formulation and preferably from 3 to 15%. The hydrocolloid for use in the powder formulation of the invention will have a viscosity of more than 50 centipoises as indicated above, and will preferably comprise cellulose polymers which are cellulose ethers such as methyl cellulose, cellulose alkyl hydroxylates such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose or hydroxyethyl cellulose, cellulose alkyl carboxylates such as carboxymethyl cellulose and carboxyethyl cellulose, and alkali metal salts of cellulose alkyl carboxylates, such as sodium carboxymethyl cellulose and sodium carboxyethyl cellulose, as well as carboxypolymethylene (molecular weight 2.5 to 3.5 million). Preferred are sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose and carboxypolymethylene. However, it is to be understood that any hydrocolloid may be employed in the present invention, such as, for example, gum acacia, guar gum, gum tragacanth, gum xanthan, an alkali metal carageenate, or mixtures thereof. Other examples of suitable hydrocolloids are set out in U. S. Patent No. 4,140,755 to Sheth et al. The sustained release powder may also include additional edible non-toxic ingredients as conventionally employed powder medicinal dosage forms. Thus, the powder of the invention may include one or more excipients in conventional amounts, such as lactose, sugar, microcrystalline cellulose, wood cellulose, mannitol, sorbitol, one or more lubricants in an amount within the range of from 0.25 to 8% by weight of the powder, and preferably from 0.5 to 5% by weight of the powder, such as magnesium stearate, stearic acid, palmitic acid, talc, carnauba wax and the like. Other conventional ingredients which may optionally be present include preservatives, stabilizers, anti-adherents or silica flow conditioners or glidants, such as Syloid brand silicon dioxide as well as FD&C colors. The powder of the invention may be loaded into conventional capsules, such as hard gelatin capsules, to form the finished formulation of the invention. Preferred controlled release powder formulations of the invention will include the following: Ingredient % by Weight Medicament (basic) (e.g., verapamil) 20 to 60 Alginic acid basic salt (such as Na alginate -viscosities ranging from 5 to 350 at 20°C in 1% solution) 15 to 45 Hydrocolloid gelling agent (such as hydroxypropylmethyl cellulose, e.g., Methocel E4M, viscosity of 4000 cps at 2% solution at 20°C) 3 to 15 Excipients qs to 100% Average particle size - 50 to 400 µ Bulk density 0.15 to 0.55 g/cm 3 Brief Description of the Figures FIGURE 1 is a graph showing verapamil dissolution profiles for tablet and powder floating capsule at 50 rpm basket speed (pH 1, 0-1 hr.; pH 7.5, 1-12 hr.); FIGURE 2 is a graph showing rate of fluid penetration into tablet and floating capsule in 0.1 M HCl; FIGURE 3 is a graph showing rate of fluid penetration into tablet and floating capsule in S.I.F. (pH 7.5); FIGURE 4 is a graph showing verapamil dissolution profiles for tablet and powder floating capsule at 100 rpm basket speed (pH 1, 0-1 hr., pH 7.5, 1-12 hr.); FIGURE 5 is a graph showing verapamil dissolution profile for tablet and powder floating capsule using disintegration apparatus; FIGURE 6 is a graph showing verapamil dissolution profiles for tablets and powder floating capsules in 0.1 M HCl at basket speed of 50 rpm. The following Examples represent preferred embodiments of the present invention. Example 1 A buoyant sustained release powder formulation capable of slowly releasing the calcium channel blocker verapamil HCl in vitro regardless of the pH of the environment for a period of up to 10 to 12 hours or more and having the following composition was prepared as described below. Ingredient Per Dosage Unit (mg) Powder Composition Verapamil hydrochloride 240 Sodium alginate (300 cps) 135 Hydroxypropylmethyl cellulose (Methocel E4M viscosity of 4000 cps) (hydrophilic polymer) 25.2 Avicel pH 101 (microcrystalline cellulose) 40.8 Lactose 8.3 Hydroxypropylmethyl cellulose (binder -Methocel E5) 4.5 Magnesium stearate (lubricant) 4.5 The verapamil raw material was first screened through a 40# sieve before the required amount for manufacture was weighed. All other excipients were screened through a 20# sieve prior to weighing. The accurately weighed powders were gradually triturated into a suitable jar which was subsequently blended for 10 minutes in a turbula mixer. Approximately 450 mg of the blended material (about 250 µm average particle size and bulk density of about 0.3 g/cm 3 ) was then filled into size 0 grey hard gelatin capsules and the fill weights accurately recorded. The following materials and methods were employed in testing the above capsules. A. Materials 1) USP XXI Simulated Intestinal Fluid without Enzymes (SIF) 6.8 g of anhydrous potassium dihydrogen orthophosphate (KH 2 PH 4 ) was dissolved into distilled water and added to a 1000 ml graduated cylinder. To this solution 190 ml of 0.2 M sodium hydroxide solution and a further 400 ml of distilled water were added. The solution was mixed thoroughly, the pH adjusted to 7.5±0.1 using 0.2 M sodium hydroxide and then diluted to the 1000 ml mark with distilled water. 2) USP XXI Hydrochloric Acid 8.8 ml of concentrated hydrochloric acid (S.G 1.18) was added to a 1000 ml graduated cylinder containing 800 ml of distilled water. The solution was then diluted to the 1000 ml mark with distilled water and mixed thoroughly. 3) Verapamil HCl Standard Solution In 0.1 M Hydrochloric Acid Into a 1000 ml volumetric flask approximately 240 mg of verapamil HCl was accurately weighed. This was dissolved in 5.00 ml of methanol, diluted to volume with 0.1 M HCl and then mixed thoroughly. In SIF The above was repeated but using SIF. 4) Verapamil Tablets For comparison of release profiles, an experimental verapamil HCl 240 mg SR tablet was used. The tablet formulation is given in Table 1. Formula of In-House Generic Verapamil SR Tablet Raw Material mg/450 mg Tablet Verapamil HCl 240.00 Methocel E4M 25.20 Manucol DMF 135.00 Avicel PH 101 40.80 Methocel E5 4.50 Magnesium Stearate 4.50 Total 450.00 Sepifilm 003 7.35 Sepisperse AP3149 6.15 B. Equipment 1) Dissolution Apparatus The rotating basket apparatus. In this test, the caleva multiple spindle model 7ST (G.B. Caleva Ltd., Dorset) was used, equipped with a temperature controlled water bath (37 ± 0.5°C) and 1000 ml round bottom pyrex glass dissolution vessels fitted with lids and sample tubes. 2) Disintegration Apparatus The Erweka 4 basket rack assembly model ZT2 (F. Copley and Sons, Nottingham) was used. This machine consisted of 4 basket rack assemblies which lowered and raised at a rate of 29 to 32 cycles/minute into the immersion fluid which was contained within a low form beaker at a temperature of between 35 and 39°C. 3) Spectrophotometer The Hewlett Packard 8452A Diode Array Spectrophotometer equipped with a 1 cm quartz cell was used to obtain all spectroscopic data. This is a single beam machine with one compartment for a reference/sample cell. C. Experimental 1) Preparation of Powder Filled Verapamil HCl 240 mg SR Capsules Capsules were prepared from the tablet formulation excluding the coating materials (Table 2). Basic Formulation Used to Produce Capsules Raw Material mg/450 mg Capsule Verapamil HCl 240.00 Methocel E4M 25.20 Manucol DMF 135.00 Avicel PH 101 40.80 Methocel E5 4.50 Magnesium Stearate 4.50 D. In-vitro Dissolution Test for Verapamil HCl 240 mg SR Tablets and Capsules Each of the six glass dissolution vessels were filled with 1000 ml of 0.1 M HCl and brought to 37 ± 0.5°C using the temperature controlled water bath. The medium was then deaerated with helium and the temperature allowed to re-equilibrate. One sample of the dosage form under investigation was placed into each basket and the test initiated by lowering the baskets into the dissolution vessels and rotating them at the pre-determined speed (50 or 100 rpm). At 30 and 60 minutes, 10 ml samples were filtered through the 0.45 micron disposable filters discarding the first 3 ml of filtrate; samples were then assayed for verapamil using the diode array spectrophotometer operating at an analytical wavelength of 260 nm and a reference wavelength of 320 nm. Immediately after the 60 min. time point in 0.1 M HCl, the baskets were raised out of the dissolution vessels. Each vessel was emptied, rinsed, dried and then filled with exactly 1000 ml of SIF and brought to 37 ± 0.5°C using the temperature controlled water bath. The medium was then deaerated with helium and the temperature allowed to re-equilibrate. The baskets were then re-lowered and the dissolution continued with 10 ml samples being removed using plastic syringes 30, 60, 90, 120, 180, 240, 300, 360, 420 and 1380 minutes after re-starting the dissolution. The samples were filtered through the 0.45 micron disposable filters discarding the first 3 ml of filtrate. Sampes were then assayed for verapamil HCl using the Diode Array Spectrophotometer operating at an analytical wavelength of 260 nm and a reference wavelength of 320 nm. The spectroscopic data was calculated to determine the percent dissolution profile. E. In-vitro Dissolution Test for Verapamil HCl 240 mg SR Dosage Forms Using a Single Medium (0.1 M HCl or SIF) Using the conditions already described in section D, dissolution tests and sample assay were performed upon the various dosage forms except that instead of employing a switch of media after 1 hour, the same media was used throughout the investigation. F. In-vitro Test for Verapamil Release from Verapamil HCl 240 mg SR Tablets and Capsules Utilizing Disintegration Apparatus Each of the four glass, flat bottomed vessels were filled with 500 ml of 0.1 M HCl and brought to 36 ± 0.5°C using the temperature controlled water bath. One sample of the dosage form under investigation was placed into a single sample tube of each rack assembly. The experiment was initiated by switching on the machine and the rack assemblies were plunged repeatedly into and out of the medium at a rate of approximately 30cyc/min. 10 ml samples were withdrawn from each vessel in a plastic syringe after 5, 10, 15, 30, 60 and 120 minutes. The samples were filtered through 0.45 micron disposable filters and analyzed and calculated as before . Results and Discussion Surprisingly, when the loose powder filled capsule formulation was exposed to the pH switching dissolution experiment (Section D) the release profile obtained was found to be similar to that of the tablet (FIGURE 1 - pH switched at 1 hour). It was also noticed that the capsules rose to the top of the baskets during the experiment, i.e., the capsules exhibited buoyant properties. It would appear that the capsule shell serves to retain the powder plug initially, however, as fluid penetrates in through the gelatin shell into the device, the polymers present hydrate to form a viscous gel layer around the dry inner core. The capsules buoyancy may be attributed to the powder blends low bulk density (0.35 gcm 3 ). Studies have shown that the capsules are capable of floating for up to 5 hours in 0.1M HCl. By this time, it is envisaged that sufficient fluid has penetrated into the device so as to remove enough air from the capsule core that the dosage form's density rises above that of the immersion fluid. Studies conducted into the penetration rate of fluid into the two devices are presented in FIGURES 2 and 3 (where dry inner core is expressed as a % of initial diameter). These diagrams show that the processes are essentially different between the two dosage forms and also between the two media. Overall, there appears to be a greater rate of fluid penetration into the capsule which is perhaps predictable due to its greater porosity. It is also noteworthy that the capsule seemingly experiences an initial expansion in the diameter of its dry inner core. Since the water penetration rates do in fact appear to be different, it would infer that this mechanism is of only minor importance to the rate of verapamil release since these have been shown to be very similar in nature. Following oral administration, the device would inevitably be exposed to more violent stresses in the gastro intestinal tract than those experienced at 50 rpm in dissolution apparatus. It is therefore pertinent to investigate how the capsules release properties compare to those of the tablet under more vigorous conditions. FIGURE 4 shows that at a basket rotation speed of 100 rpm (pH switched at 1 hour), the two devices once again exhibit similar release profiles. The rate of drug release is increased by approximately the same amount in the two dosage forms. This greater rate of drug release may be attributed to factors such as more rapid diffusion of drug out of the matrix and increased erosion of the device. The former effect would arise due to the smaller diffusion layer thickness and the latter effect due to increased frictional forces on the device. Under the conditions present within disintegration apparatus, there is a greater initial burst in verapamil release from the capsule formulation, however, the release rates then appear to become very similar in nature over the two hour test period (FIGURE 5; experiment performed in 0.1 M HCl). Example 2 A buoyant propranolol powder capsule in accordance with the present invention is prepared following the procedure of Example 1 except substituting propranolol for the verapamil hydrochloride. Example 3 A buoyant trifluoperazine HCl powder capsule in accordance with the present invention is prepared following the procedure of Example 1 except substituting trifluoperazine HCl for the verapamil hydrochloride. Example 4 A buoyant diltiazem HCl powder capsule in accordance with the present invention is prepared following the procedure of Example 1 except substituting diltiazem HCl for the verapamil hydrochloride. It will be understood that with respect to the formulations prepared in Examples 2, 3 and 4, the ratio of HPMC/alginate and viscosity grade of alginate may be modified to yield drug release more or less independent of environmental pH, consistent with the in vivo needs of the product. Example 5 A buoyant metoprolol tartrate salt powder capsule in accordance with the present invention is prepared following the procedure of Example 1 except substituting metoprolol tartrate for verapamil hydrochloride. Example 6 A buoyant verapamil powder capsule containing sodium alginates of different viscosities having the following composition was prepared as described in Example 1. Ingredient Amount/Powder capsule mg Verapamil HCl 240 Sodium alginate 9 cps (measured at 20°C in 1% solution) 90 Sodium alginate 300 cps (measured at 20°C in 1% solution) 45 Hydroxypropylmethylcellulose 4000 cps (E4M) 45 Hydroxypropylmethyl cellulose 5 cps (E5) 9 Microcrystalline cellulose 33.2 Lactose BP 8.3 Magnesium stearate 4.5 450.0 mg The powder has a 250 µm average particle size and a bulk density of 0.35 g/cm 3 .

Claims: A buoyant controlled release pharmaceutical formulation in the form of a capsule containing a powder, from which a pharmaceutical of a basic character is released at a controlled rate irrespective of the pH of the environment, the formulation comprising a pharmaceutical of a basic character, a pH-dependent polymer which is a salt of a polyuronic acid, and which is present in an amount not exceeding 45% by weight of the formulation; a pH-independent hydrocolloid gelling agent having a viscosity of from 50 to 100,000 mPas (centipoises) in 2% solution at 20°C, and which is present in an amount not exceeding 35% by weight of the formulation, said formulation being free of calcium ion and carbon dioxide-producing material and will float in gastric juices. The formulation as defined in Claim 1 having a bulk density of within the range of from 0.1 to 0.8 g/cm 3 . The formulation as defined in Claim 1 or 2 having an average particle size of within the range of from 25 to 1000 µm. The formulation as defined in Claim 1, 2 or 3 wherein the pH-dependent salt of a polyuronic acid is employed in a weight ratio to the pH-independent hydrocolloid gelling agent of within the range of from 0.1:1 to 10:1. The formulation as defined in Claim 1, 2, 3 or 4 wherein said pH-dependent salt of a polyuronic acid is employed in an amount within the range of from 15 to 45% by weight of the formulation and the pH-independent hydrocolloid gelling agent is employed in an amount within the range of from 5 to 20% by weight of said formulation. The formulation as defined in any preceding claim wherein said pharmaceutical of a basic character is employed in an amount not exceeding 75% by weight of said formulation. The formulation as defined in any preceding claim wherein the powder comprises a binder. The formulation as defined in any preceding claim wherein said pharmaceutical of a basic character is a calcium antagonist. The formulation as defined in Claim 8 wherein said calcium antagonist is a salt of verapamil, a salt of diltiazem, a salt of nicardipine, a salt of nifedipine, a salt of gallapomil or a salt of cinnarizine. The formulation as defined in any one of Claims 1-7 wherein said pharmaceutical of a basic character is a beta blocker, antihistamine, sympathomimetic, beta adrenergic agonist or bronchodilator, or central nervous system drug. The formulation as defined in Claim 10 wherein said beta blocker is a salt of propranolol, a salt of metoprolol, or a salt of nadolol, said antihistamine is a salt of chlorpheniramine, a salt of diphenhydramine, said sympathomimetic is a salt of phenylpropanolamine or a salt of pseudoephedrine, said beta adrenergic agonist is a salt of albuterol, fenoterol, or a salt of terbutaline, and said central nervous system drug is a salt of thioridazine, a salt of trifluoperazine, chlorpromazine, BMS 181101 BMY 14,802, buspirone, nefazadone, gepirone, tiospirone. The formulation as defined in any preceding claim wherein said hydrocolloid gelling agent is hydroxypropylmethyl cellulose, methyl cellulose, hydroxypropyl cellulose, or a mixture of two or more of such hydrocolloid gelling agents. The formulation as defined in any preceding claim wherein said salt of a polyuronic acid is a salt of alginic acid. The formulation as defined in Claim 13 wherein said salt of alginic acid is sodium alginate or potassium alginate. The formulation as defined in Claim 13 or 14 wherein the salt of alginic acid has a viscosity of within the range of from 4 to 300 mPas (centipoises) in 1% solution at 25°C. The formulation as defined in Claim 13, 14 or 15 containing alginic acid salts of two different viscosities. The formulation as defined in Claim 1 wherein said pharmaceutical of a basic character is verapamil hydrochloride, said salt of alginic acid is sodium alginate, said hydrocolloid gelling agent is hydroxypropylmethyl cellulose having a viscosity of from 50 to 100,000 mPas (centipoises), said binder is hydroxypropylmethyl cellulose having a viscosity of from 5 to 15 mPas (centipoises). The formulation as defined in any preceding claim wherein the powder is free-flowing before encapsulation.

Inventors: DENNIS ANDREW, LEE KEVIN, TIMMINS PETER, DENNIS, ANDREW, LEE, KEVIN, TIMMINS, PETER
Applicants: SQUIBB & SONS INC, E.R. SQUIBB & SONS, INC.
Application year: 1992
Main classification: A61K9
IPC codes: A61K47, A61K9