AU9168791A

AU9168791A - Polyamine drug-resin complexes

Info

Publication number: AU9168791A
Application number: AU91687/91A
Authority: AU
Inventors: Anthony Earl Carpanzano; William Joseph Kelleher
Original assignee: Richardson Vicks Inc
Current assignee: Richardson Vicks Inc
Priority date: 1990-12-21
Filing date: 1991-12-16
Publication date: 1992-07-22
Anticipated expiration: 2011-12-16
Also published as: BR9107173A; WO1992011038A1; FI932842A0; CN1063221A; FI932842A; AU663695B2; HU9301819D0; JPH06504059A; MY107811A; CZ119793A3; HUT74642A; IE914513A1; SK59493A3; NO932212D0; CA2098200A1; NZ241097A; EP0563294A1; NO932212L; MX9102753A; PT99912A

Description

POLYAMINE DRUG-RESIN COMPLEXES

TECHNICAL FIELD

The present invention relates to oral pharmaceutical preparations which comprise a pharmacologically-active polyamine drug bound to a cation-exchange resin to provide a drug-resin complex having a drug content greater than one equivalent of amine per equivalent of cation-exchange capacity. The drug-resin complex is optionally coated with a water-permeable diffusion barrier coating that is insoluble in gastrointestinal fluids thereby providing a controllable release of drug under conditions encountered in the gastrointestinal tract.

BACKGROUND OF THE INVENTION

Sustained or prolonged-release dosage forms provide a controlled and constant supply of drug to an organism. The control of cough, sleep, enuresis, and migraine headaches are all benefits obtained from such a controlled release of a specific drug. Additionally, controlled release of antimicrobials can be obtained through such a dosage form. Such a controlled release of drugs eliminates the need to interrupt sleep to take medication, and can also prevent missed doses. They also provide the convenience of daytime dosing where the dosage form can be taken first thing in the morning and provide therapeutic levels of the drug throughout the day.

A controlled drug-release system delivers drugs in a manner that will maintain therapeutically effective plasma levels over a period of time that is significantly longer than that which is given by a typical drug dosage form.

Uncoated ion-exchange resin-drug complexes which delay release of a drug in the gastrointestinal tract are described in U.S. Patent No. 4,788,055 and 2,990,332. However, such uncoated complexes provide only a relatively short delay of drug release in comparison with the preparations of this invention and provide poor control of drug release because the control is limited to variation in particle size and cross-linkage of the sulfonic acid-type resin used to prepare the adsorption compounds. Various coated resin-drug complexes have been reported (e.g., in U.S. Patent Nos. 3,138,525; 3,499,960; and 3,594,470; Belgian Patent No. 729,827; German Patent No. 2,246,037; and Borodkins et al., Journal of Pharmaceutical Science. Vol. 60, pages 1523-1527, 1971), but none are believed to employ the preparations of the subject invention or to provide the controllable release obtained with the present preparations.

The present invention provides controlled-release pharmaceutical compositions obtained by complexing greater than one equivalent of a polyamine drug with a pharmaceutically acceptable cation-exchange resin and optionally coating such complexes with a substance that will act as a barrier to control the diffusion of the drug from its core complex into the gastrointestinal fluids.

It is known that the pharmaceutically acceptable resins and their drug complexes can undergo significant swelling (up to about a 60% increase in volume) when the dry, non-hydrated form is placed in contact with gastrointestinal fluids.

When the coated drug-resin complex is suspended in an aqueous dosage form or when it contacts gastrointestinal fluids, it expands to its swollen state, and in doing so, ruptures the diffusion barrier coating. The result is loss of control of the diffusion of released drug.

Controlled-release drugs for use in the gastrointestinal tract are described in U.S. Patent Numbers 4,847,077, and 4,221,778, and European Patent Application 254,811, all to Raghunathan; and European Patent Application 254,822, to Chow et al. The method described therein for preparing products having controlled release properties involved a three-step process: (i) preparation of a drug-resin complex; (ii) treating this complex with a suitable Impregnating agent; and (iii) coating the particles of treated complex with a water-permeable diffusion barrier. European Patent Application 249,949, to Sellassie et al. describes three-component coated complexes containing a neutral polymeric binder such as hydroxypropylcellulose. All of these drug-resin complexes have the disadvantage of requiring that the drug-resin complex be treated with an impregnating agent or binder in order to achieve the desired control of release of drug when placed in contact with aqueous fluids such as are found in the gastrointestinal tract.

Coated drug-resin complexes, which do not require any such impregnation, and yet which do not undergo swelling sufficient to rupture the diffusion barrier coating when placed in contact with an aqueous vehicle or with gastrointestinal fluids, are described in European Patent Application Number 367,746, to Kelleher, W.J. et al., published May 9, 1990. This document is incorporated herein in its entirety by reference.

The primary concern in the design of control led-release drug delivery systems has been with delaying the release or dissolution of the active drug under the conditions which exist in the gastrointestinal tract. Early evaluation of candidate delivery systems are most often performed with the use of simulated gastric and intestinal fluids. See, USP XXII The United States Pharmacopeia, pp. 1788-1789 (1990), which is incorporated by reference herein. Having achieved a desired in vitro release rate, the second concern is with the extent or completeness of release or dissolution, within a time frame that is reasonably consistent with the transit time through the entire alimentary canal.

A certain category of drugs presents difficulties in this latter respect when used with ion-exchange resin-based controlled release systems: these are basic drugs with more than one amine functional group, i.e. polyamine drugs. A tenet of ion-exchange technology is that the strength of the binding is increased as the number of binding sites on a molecule is increased. A negative consequence of this strengthened binding is that drug molecules bound by two or more sites might be released too slowly or incompletely under conditions encountered in the gastrointestinal tract. An illustrative example is provided by Amsel et al., Pharmaceutical Technology. April, 1984, pages 28-48, this document being incorporated herein by reference, wherein the results of a pharmacokinetic study of a liquid suspension containing coated codeine resinate particles and uncoated chlorpheniramine resinate particles were reported. Codeine is a monoamine (MW 299 and equivalent weight 299); its release into 0.1N HCl from coated resinate particles was described as being adequate. Chlorpheniramine is a diamine (HW 275 and equivalent weight 137.5); its release into 0.1N HCl was not adequate despite the fact that its resinate particles had no coating. In order to match the release profile given in 0.1N HCl by the coated codeine resinate, the relatively severe and nonphysiologic release medium consisting of 0.4H KCl had to be employed. The inadequacy of the loading dose of chlorpheniramine is borne out by the increased time taken to reach peak plasma concentrations: 5.9 hours for the resinate versus 3.6 hours for the drug administered in solution.

The most obvious way of achieving a loading dose is to incorporate unbound polyamine drug into the dosage form. A negative consequence of having this unbound material is that the formulation would suffer from the disadvantage of having an unpleasant taste, since many polyamine drugs have a bitter, unpalatable taste.

It is another tenet of ion-exchange technology that binding is on an equivalent-to-equivalent basis, just as is the case for acid-base reactions. A negative consequence of this is that for a basic drug with an equivalent weight of only 120 (e.g., pheniramine), even drug loads which approach 100% of the binding capacity of the resin will fall to meet the minimum load needed to insure the integrity of the optional coating of the present invention with non-impregnated complexes.

The polyamine drug resin complexes of the instant invention overcome these delivery and taste-masking problems. Without being limited by theory, it is believed that by binding more than one equivalent of a polyamine drug to a cation-exchange resin (i.e. in a ratio of greater than one equivalent of amine per equivalent of cation-exchange capacity) it would be possible to provide drug-resin complexes which provide both an immediate release of the drug present in excess of one equivalent and a slower or sustained release of the remaining drug. In other words, each polyamine drug molecule would be bound to the resin substantially by only one of its amine groups and would therefore occupy only one binding site on the resin. When coupled with an optional water-insoluble barrier diffusion coating, such coated polyamine drug-resin complexes would provide additional control over the release profile. The polyamine drug-resin complexes of the instant invention, when added to gastrointestinal fluids will (i) rapidly release a portion of the polyamine drug bound in excess of 1 equivlaent, (ii) release the remaining portion of drug at a slower rate so as to provide a sustaining dose, and (iii) release a total amount of drug that is substantially in excess of the total amount released from a resin complex which contains the same polyamine drug loaded at a level of one equivalent or less per equivalent of cation-exchange capacity.

It is therefore an object of the present invention to provide a polyamine drug-resin complex, containing a polyamine drug loading greater than one equivalent of amine per equivalent of cation-exchange capacity, which provides a controllable release of drug under conditions encountered in the gastrointestinal tract.

It is a further object of the present invention to provide a polyamine drug-resin complex, containing a polyamine drug loading greater than one equivalent of amine per equivalent of cation-exchange capacity, which provides an immediate release of the polyamine drug bound in excess of one equivalent and a slower release of the remaining polyamine drug under conditions encountered in the gastrointestinal tract.

It is another object of the present invention to provide a polyamine drug-resin complex, containing a polyamine drug loading greater than one equivalent of amine per equivalent of cation-exchange capacity and which is also optionally coated with a water-permeable diffusion barrier coating that is insoluble in gastrointestinal fluids, which provides a controllable release of drug under conditions encountered in the gastrointestinal tract.

It is yet another object of the present invention to provide a polyamine drug-resin complex which provides a taste-masking benefit.

These and other objects of this invention will become apparent in light of the following disclosure.

SUMMARY OF THE INVENTION

An oral pharmaceutical composition in unit dosage form comprising cation-exchange resin particles ranging from about 10 to about

500 microns, said particles having a pharmacologically-active polyamine drug bound thereto at a capacity greater than 1 equivalent of amine per equivalent of cation-exchange capacity, wherein said composition provides controlled release of said active drug.

All percentages and ratios used herein are by weight and all measurements are at 25°C, unless otherwise indicated.

DESCRIPTION OF THE INVENTION.

As used herein, the term water-permeable is used to indicate that the fluids of the alimentary canal will permeate or penetrate the optional barrier coating film with or without dissolving the film or parts of the film. Depending on the permeability or solubility of the chosen coating (polymer or polymer mixture) a lighter or heavier application thereof is required so that the drug does not leach out from the complex to an extent of more than 4% in artificial saliva at 20-40°C in 2 minutes.

As used herein, the term regularly shaped particles refer to those particles which substantially conform to geometric shapes such as spherical, elliptical, cylindrical and the like. These shapes are ordered according to established geometric principles. For example, regularly shaped ion-exchange resins of this type are exemplified by Dow XYS-40010.00 (supplied by Dow Chemical Company), and to the drug-resin complexes formed by binding drugs to these resins.

As used herein, the term irregularly shaped particles refers to those particles excluded from the above definition, such as those particles with amorphous shapes with increased surface areas due to surface area channels or distortions. For example, irregularly shaped ion-exchange resins of this type are exemplified by Amberlite IRP-69 (supplied by Rohm and Haas), and to the drug-resin complexes formed by binding drugs to these resins.

As used herein, the term meq is an abbreviation for milllequlvalent(s).

The drugs that are suitable for use in these preparations are basic, having at least two amino or substituted amino moieties available for binding. Examples of drugs useful in the present invention include, but are not limited to, acetophenazine, amitriptyline, brompheniramine, carbinoxamine, chlorcyclizine, chlorpheniramine, chlorpromazine, clonidine, cyclizine, desipramine, dexbrompheniramine, dexchlorpheniramine, doxylamine, ergotamine, fluphenazine, hydroxychloroquine, hydroxyzine, imipramine, meclizine, mesoridazine, methdilazine, methysergide, pheniramine, pyrilamine, tripelennamine, triprolidine, promazine, and quinidine, and mixtures thereof.

The ion-exchange resins suitable for use in these preparations are water-insoluble and consist of a pharmacologically inert organic or inorganic matrix containing covalently bound functional groups that are ionic or capable of being ionized under the appropriate conditions of pH. The organic matrix may be synthetic (e.g., polymers or copolymers of acrylic add, methacrylic acid, sulfonated styrene, sulfonated divinylbenzene), or partially synthetic (e.g., modified cellulose and dextrans). The inorganic matrix can also be, e.g., silica gel modified by the addition of ionic groups. The covalently bound ionic groups may be strongly acidic (e.g., sulfonic add) or weakly acidic (e.g., carboxylic add). In general, those types of cation-exchangers suitable for use in ion-exchange chromatography and for such applications as deionization of water are suitable for use in these controlled release drug preparations. Such ion-exchangers are described by H.F. Walton in "Principles of Ion Exchange" (pp. 312-343) and "Techniques and Applications of Ion-Exchange Chromatography" (pp. 344-361) in Chromatography. (E. Heftmann, editor), Van Nostrand Reinhold Company, New York (1975), incorporated by reference herein. The cation-exchange resins useful in the present invention preferably have exchange capacities below about 6 meq/gram and more preferably below about 5.5 meq/gram. Preferably, these cation-exchange resins contain covalently bound ionic groups which are strongly acidic.

The size of the ion-exchange particles should preferably fall within the range of about 40 microns to about 150 microns. Particle sizes substantially below the lower limit are difficult to handle in all steps of the processing. Particle sizes substantially above the upper limit, e.g., commercially-available ion-exchange resins having a spherical shape and diameters up to about 1000 microns, are gritty in liquid dosage forms and have a greater tendency to fracture when subjected to drying-hydrating cycles. Moreover, it is believed that the increased distance that a displacing ion must travel in its diffusion into these large particles, and the increased distance the displaced drug must travel in its diffusion out of these large particles, cause a measurable but not readily controlled prolongation of release even when the drug-resin complexes are uncoated.

Representative resins useful in this invention include Amberlite IRP-69 (obtained from Rohm and Haas) and Dow XYS-40010.00 (obtained from The Dow Chemical Company). Both are sulfonated polymers composed of polystyrene cross-linked with 8% of divinylbenzene, with an ion-exchange capacity of about 4.5 to 5.5 meq/gram of dry resin (H⁺-form). Their essential difference is in physical form. Amberlite IRP-69 consists of irregularly-shaped particles with a size range of 47 microns to 149 microns, produced by milling the parent large-sized spheres of Amberlite IRP-120. The Dow XYS-40010.00 product consists of spherical particles with a size range of 45 microns to 150 microns.

The binding may be performed, for example, as a batch or column process, as is known in the art. In most of the illustrative examples described below, the drug-resin complexes are prepared by a batch process. The drug-resin complex thus formed is collected by filtration and washed with ethanol and/or water to insure removal of any unbound drug. The complexes are usually air-dried in trays at room temperature.

Further control of the release of drugs from drug-resin complexes has been achieved by the direct application of an optional diffusion barrier coating to particles of such complexes, provided that the drug content of the complexes is above a critical value. Any coating procedure which provides a contiguous coating on each particle of drug-resin complex without significant agglomeration of particles may be used. In the illustrative examples below, the coatings were applied with a fluid-bed coating apparatus having the Wurster configuration.

The coating materials may be any of a large number of natural or synthetic film-formers used singly, in admixture with each other, and in admixture with plasticizers, pigments and other substances to alter the characteristics of the coating. In general, the major components of the coating should be insoluble in, and permeable to water. However, it might be desirable to incorporate a water-soluble substance, such as methyl cellulose, to alter the permeability of the coating, or to incorporate an acid-insoluble, base-soluble substance to act as an enteric coating. The coating materials may be applied as a suspension in an aqueous fluid or as a solution in organic solvents. Suitable examples of such coating materials are described by R.C. Rowe in Materials used in Pharmaceutical Formulation. (A.T. Florence, editor), Blackwell Scientific Publications, Oxford, 1-36 (1984), incorporated by reference herein. Preferably the water-permeable diffusion barrier is selected from the group consisting of ethyl cellulose, methyl cellulose, and mixtures thereof.

The coated drug-resin particles prepared according to the teachings of this invention are suitable for suspending in an essentially aqueous vehicle with the only restrictions on its composition being (i) an absence of, or very low levels of ionic ingredients, and (ii) a limitation on the concentrations of water-miscible organic solvents, such as alcohol, to those levels which do not cause dissolution of the diffusion barrier coating. These coated drug-resin particles are also suitable for placing into capsules as a solid dosage form.

TEST METHOD

Moisture determinations were performed with a Mettler LP16 infrared heater on a PE160 balance. Because of the variation in moisture content over relatively short time periods, moisture determinations were always performed immediately prior to the use of any resin or drug-resin complex, and corrections were made in quantities taken so that all values are expressed on a dry weight basis.

Immediately after preparation, all drug-resin complexes were washed with an appropriate solvent to insure removal of unbound drug. When the salt forms of drugs were used in the binding mixture, water was used to wash the complex. When the free base forms of the drugs were used in the binding mixture, ethanol was used to wash the complex. Washing was continued in a batch or percolation mode until the washings were shown by spectrophotometric measurements to be essentially free of drug.

All complexes were analyzed for drug content by adding an accurately weighed sample (about 500 mg) to a 200 mL volumetric flack containing 100 mL of 0.5 M sodium acetate in 90% ethanol and heating the mixture at reflux for one hour. The mixture was allowed to cool to room temperature and was diluted to 200 mL with ethanol. An aliquot was removed from the clear supernatant after settling or centrifugation. After appropriate dilution, the drug content of the supernatant was determined spectrophotometrically. Drug content of the complex was expressed as weight percentage based on the free base form of the drug, unless otherwise indicated.

Determinations of release of drug from drug-resin complexes were performed with equipment that conforms to the USP Dissolution Apparatus 2. In all instances, a two-bladed paddle rotating at 50 rpm was used. The release medium was either 900 mL of 0.1 N HCl or 0.1 N HCl converted in situ to 0.07 M sodium phosphate buffer (pH 7.2), by adding 24.8 g of trisodium phosphate dodecahydrate to 900 mL of 0.1 N HCl. Release media were maintained at 37°C. Sufficient drug-resin complexes were added to provide the following doses (expressed as the commonly administered forms): doxylamine succinate, 15 mg; chlorpheniramine maleate, 16 mg; and pheniramine maleate, 25 mg. The drug-resin complexes were added to the release media as dry powders. At appropriate time Intervals, samples of approximately 10 mL were removed from the dissolution beaker and immediately filtered through a syringe-mounted filter. Exactly 5.0 mL of the filtrate was reserved for analysis. The remainder of the filtrate was returned to the dissolution beaker. Particles of drug-resin complex adhering to the filter were rinsed into the dissolution beaker with exactly 5.0 mL of fresh release medium. The absorbances of the filtered samples were measured at the wavelength of the peak in the ultraviolet spectrum with a Perkin-Elmer model 552 or Lambda 3B UV/VIS spectrophotometer. The absorbance values were converted to percentages of added drug that were released. Alternatively, the samples were analyzed by HPLC on a reverse phase phenyl column using methanol:water:acetic add (60:40:2 by volume, with 5 mM sodium hexane sulfonate) with a Waters model 6000A pump and a model 450 variable wavelength detector set at the wavelength of peak absorption for the drug. Peak areas were converted to percentage of drug released. Diffusion barrier coatings were applied with a Glatt CPCG-5 Wurster-type fluid-bed coater. The following were the conditions used in a typical coating procedure: inlet air temperature, 70°C; atomizatlon air pressure, 60 psi; spray rate, 20-25 g/min; outlet air temperature, 40-50°C. Microscopic examination of the coated particles was performed with a transmission and stereo light microscope.

The level of coating contained on the coated drug-resin complex was determined by stripping the coating with an appropriate solvent, evaporating the solvent, and weighing the dried residue. An accurately weighed sample of coated drug-resin complex of about 2.0 g was placed in a 30-mL glass centrifuge tube. Twenty mL of ethanol was added and the mixture was stirred occasionally over a period of about 30 minutes. The mixture was centrifuged and the supernatant was decanted into a round bottom flask. The extraction, centrifugation and decanting were repeated three more times. The combined ethanolic extracts were concentrated to dryness in a rotary vacuum evaporator. The flask containing the dried residue was rinsed four times, each with several mL of methylene chloride/acetone (9:1 v/v). The rinsings were transferred to a tared aluminum pan and allowed to evaporate in a hood. The pan was heated at 55°C for 30 minutes, allowed to cool, and weighed. The increase over the tare weight was attributed to the ethylcellulose coating. The values obtained agreed very well with the amount of coating applied in the fluid-bed coater.

The following examples illustrate embodiments of the subject invention wherein both essential and optional ingredients are combined.

EXAMPLE I

This example illustrates a drug-resin complex comprising doxylamine bound to an Amberlite IRP-69 resin. This drug-resin complex contains 1.92 equivalents of doxylamine per equivalent of cation-exchange capacity. The release profile for this drug-resin complex in simulated gastric fluid is compared to that for a doxylamine complex containing less than 1 equivalent of drug per equivalent of cation-exchange capacity.

(A). Preparation of a doxylamine-Amberlite IRP-69 complex having 1.92 equivalents of doxylamine per equivalent of cation-exchange capacity.

Amberlite IRP-69 (H⁺-form) 3.556 g

Doxylamine (Free Base) 5.000 g

The resin is added to a round bottom flask, which is fitted with a condenser, and which contains 50 mL of water, pre-warmed to

100°C. The doxylamine (free base) is added and the mixture is held at 100°C with mixing for 2 hours. The mixture is suction filtered and the retained drug-resin cake is washed with ethanol until the washings have a negligible absorbance at 261 nm. The drug-resin complex, which has now been washed free of unbound drug, is dried at room temperature. Analysis shows that the complex contains 57.0% by weight of doxylamine.

(B). Preparation of a doxylamine-Amberlite IRP-69 complex having 0.976 equivalents of doxylamine per equivalent of cation-exchange capacity.

Amberlite IRP-69 (H⁺-form) 2.500 g

Doxylamine succinate 2.476 g

The resin, is added to a round bottom flask containing 20 mL of water, pre-warmed to 60°C. The doxylamine succinate is added and the mixture is held at 60°C with mixing for 2 hours. The mixture is suction filtered and the retained drug-resin cake is washed with water until the washings have a negligible absorbance at 261 nm. The drug-resin complex, which has now been washed free of unbound drug, is dried at room temperature. Analysis shows that the complex contains 40.2% by weight of doxylamine.

(C). The complexes from (A) and (B) of this example are found to give the following release profiles for doxylamine when placed in 0.1 N HCl (simulated gastric fluid). The release of doxylamine from complex (A) is substantially greater than from complex (B).

% Doxylamine Released in 0.1 N HCl

Time (minutes) Complex (A) Complex (B)

15 68 41

30 69 43

60 68 45

120 68 48

180 68 49

EXAMPLE II

This example illustrates a drug-resin complex comprising pheniramine bound to an Amberlite IRP-69 resin. This drug-resin complex contains 1.93 equivalents of pheniramine per equivalent of cation-exchange capacity. The release profile for this drug-resin complex in simulated gastric fluid is compared to that for a pheniramine complex containing less than 1 equivalent of drug per equivalent of cation-exchange capacity.

(A). Preparation of a pheniramine-Amberlite IRP-69 complex having 1.93 equivalents of pheniramine per equivalent of cation-exchange capacity.

Amberlite IRP-69 (H⁺-form) 0.500 g

Pheniramine (Free Base) 0.632 g

The resin is added to a round bottom flask, which is fitted with a condenser, and which contains 25 mL of water, pre-warmed to

100°C. The pheniramine (free base) is added and the mixture is held at 100°C with mixing for 3 hours. The mixture is suction filtered and the retained drug-resin cake is washed with ethanol until the washings have a negligible absorbance at 260 nm. The drug-resin complex, which has now been washed free of unbound drug, is dried at room temperature. Analysis shows that the complex contains 54.2% by weight of pheniramine.

(B). Preparation of a pheniramine-Amberlite IRP-69 complex having 0.91 equivalents of pheniramine per equivalent of cation-exchange capacity.

Amberlite IRP-69 (H⁺-form) 1.000 g

Pheniramine Maleate 0.927 g

The resin is added to a round bottom flask containing 10 mL of water, pre-warmed to 60°C. The pheniramine maleate is added and the mixture is held at 60°C with mixing for 3 hours. The mixture is suction filtered and the retained drug-resin cake is washed with water until the washings have a negligible absorbance at 260 nm. The drug-resin complex, which has now been washed free of unbound drug, is dried at room temperature. Analysis shows that the complex contains 35.9% by weight of pheniramine. (C). The complexes from (A) and (B) of this example are found to give the following release profiles for pheniramine when placed in 0.1 N HCl (simulated gastric fluid). The release of pheniramine from complex (A) is substantially greater than from complex (B).

% Pheniramine Released in 0.1 N HCl

Time (minutes) Complex (A) Complex (B)

15 69 35

30 69 37

60 70 39 120 70 41

180 72 41

EXAMPLE III

This example illustrates a drug-resin complex comprising chlorpheniramine bound to an Amberlite IRP-69 resin and the effect of subsequently coating the resin with a diffusion barrier coating. These drug-resin complexes (both uncoated and coated) contain 1.72 equivalents of chlorpheniramine per equivalent of cation-exchange capacity. The release profiles for these drug-resin complexes in simulated gastric fluid are compared to those for chlorpheniramine complexes (both uncoated and coated) containing less than 1 equivalent of drug per equivalent of cation-exchange capacity.

(A). Preparation of a chlorpheniramine-Amberlite IRP-69 complex having 1.72 equivalents of chlorpheniramine per equivalent of cation-exchange capacity.

Amberlite IRP-69 Resin (H⁺-form) 1250 g Chlorpheniramine (Free Base) 1759 g The resin is added to a 70 L round bottom flask containing 15 L of water pre-warmed to 70°C. The chlorpheniramine (free base) is added and the temperature is increased to 85°C and the mixture is stirred for one hour. The contents of the flask are transferred to a 20 L polyethylene bucket and allowed to stand at room temperature until most of the complex has settled. The supernatant liquid containing suspended fine particles is decanted and discarded. The sedimented complex is slurried with 2.5 L of ethanol, and the slurry is suction filtered. The drug-resin cake retained on the filter is washed with 5 L of ethanol. The washed drug-resin cake is slurried with 3 L of ethanol, and the slurry is suction filtered. The drug-resin cake retained on the filter is washed with 4.5 L of ethanol. The final washing is found to have a negligible absorbance at 264 nm. The washed drug-resin cake is spread out to dry at room temperature. Analysis shows that the complex contains 54.7% by weight of chlorpheniramine.

(B). Coating of the chlorpheniramine-Amberlite IRP-69 complex from (A) above.

Chlorpheniramine-Amberlite IRP-69 Complex 1000 g Ethyl Cellulose, N-10 100 g

Ethyl Acetate 1900 g The ethyl cellulose is dissolved in the ethyl acetate with stirring. The resin complex is placed in a pre-warmed fluid-bed coating apparatus and fluidized with 70°C intake air. The coating solution is applied at a rate of 20-25 g/minute until 2000 g has been applied. Fluidization is continued with the heated air for 2 minutes after the termination of the application of the coating solution.

(C). Preparation of a chlorpheniramine-Amberlite IRP-69 complex having 0.92 equivalents of chlorpheniramine per equivalent of cation-exchange capacity.

Amberlite IRP-69 Resin (H⁺-form) 1500 g Chlorpheniramine Maleate 1495 g

The resin is added to a 70 L round bottom flask containing 15 L of water pre-warmed to 60°C. The chlorpheniramine maleate is added and the mixture is stirred for one hour at 60°C. The contents of the flask are transferred to a 20 L polyethylene bucket and allowed to stand at room temperature until most of the complex has settled. The supernatant liquid containing suspended fine particles is decanted and discarded. The sedimented complex is slurried with 3.0 L of water, and the slurry is suction filtered. The drug-resin cake retained on the filter is washed with water (3 × 1 L). The washed drug-resin cake is further washed with 5 L of ethanol. The final washing is found to have a negligible absorbance at 264 nm. The washed drug-resin cake is spread out to dry at room temperature. Analysis shows that the complex contains 39.2% by weight of chlorpheniramine.

(D). Coating of the chlorpheniramine-Amberlite IRP-69 complex from (C) above.

Chlorpheniramine-Amberlite IRP-69 Complex 1000 g Ethyl Cellulose, N-10 100 g

Ethyl Acetate 1900 g

The ethyl cellulose is dissolved in the ethyl acetate with stirring. The resin complex is placed in a pre-warmed fluid-bed coating apparatus and fluidized with 70°C intake air. The coating solution is applied at a rate of 20-25 g/minute until 2000 g has been applied. Fluidization is continued with the heated air for 2 minutes after the termination of the application of the coating solution.

(E). The complexes from (A), (B), (C), and (D) of this example are found to give the following release profiles for chlorpheniramine when placed in 0.1 N HCl (simulated gastric fluid). The release of chlorpheniramine from uncoated complex (A) is substantially greater than from uncoated complex (C). Moreover, the uncoated complex from (A) can be successfully coated with a diffusion barrier coating to provide a sustained release of drug as exemplified by the coated complex from (B).

%Chlorpheniramine Released in 0.1 N HCl Complex (A) Complex (B) Complex (C) Complex (D)

Time (min.) (Uncoated) (Coated) (Uncoated) (Coated)

15 58 15 19 5

30 61 23 24 9

60 63 32 26 14

120 63 38 28 18

180 62 41 29 21

240 62 43 30 23

360 63 46 31 25

EXAMPLE IV

This example illustrates the preparation of a chlorpheniramine-Dow XYS Resin complex and the determination of its sequential release of chlorpheniramine into simulated gastric fluid and pH 7.2 buffer.

A. Preparation of a chlorpheniramine-Dow XYS Resin complex having 1.56 equivalents of chlorpheniramine per equivalent of cation-exchange capacity.

DOW XYS 40010.00 Resin (H⁺-form) 5.000 g Chlorpheniramine (Free Base) 7.227 g The resin is added to a round bottom flask, which is fitted with a condenser, and which contains 50 mL of water pre-warmed to

100°C. The chlorpheniramine (free base) is added and the mixture is held at 100°C with mixing for 2 hours. The mixture is suction filtered and the retained drug-resin cake is washed with ethanol until the washings have a negligible absorbance at 264 nm. The drug-resin complex, which has now been washed free of unbound drug, is dried at room temperature. Analysis shows that the complex contains 53.0% by weight of chlorpheniramine.

(B). The complex from (A) is found to give the following release profile for chlorpheniramine. The release is determined in 0.1 N HCl (simulated gastric fluid) for 60 minutes and then in pH 7.2 phosphate buffer for an additional 60 minutes. The release of chlorpheniramine into the simulated gastric fluid during the first 60 minutes is similar to the release observed for the drug resin complexes described in Examples I (A), II (A), and III (A). The change to the pH 7.2 buffer gives a total release of the remaining bound chlorpheniramine.

% Chlorpheniramine Released

Time (minutes) Complex (A)

(0.1 N HCl)

15 60

30 68

60 72

(pH 7.2 phosphate buffer)

75 90

90 98

120 103

WHAT IS CLAIMED IS:

Claims

1. An oral pharmaceutical composition in unit dosage form comprising cation-exchange resin particles ranging from about 10 to about 500 microns, said particles having a pharmacologically-active polyamine drug bound thereto at a capacity greater than 1 equivalent of amine per equivalent of cation-exchange capacity, wherein said composition provides controlled release of said active drug.

2. A pharmaceutical composition according to Claim 1 wherein said particles range from about 35 microns to about 150 microns.

3. A pharmaceutical composition according to Claim 2 wherein said particles range from about 40 microns to about 80 microns.

4. A pharmaceutical composition according to Claim 3 wherein said drug-resin complex further comprises, from about 1.5% to about 25% by weight of the drug-resin complex, of a water-permeable diffusion barrier coating.

5. A pharmaceutical composition according to Claim 4 wherein said water-permeable diffusion barrier coating is selected from the group consisting of ethyl cellulose, methyl cellulose and mixtures thereof.

6. A pharmaceutical composition according to Claim 5 wherein said pharmacologically-active polyamine drug is selected from the group consisting of acetophenazine, amitriptyline, brompheniramine, carbinoxamine, chlorcyclizine, chlorpheniramine, chlorpromazine, clonidine, cyclizine, desipramine, dexbrompheniramine, dexchlorpheniramine, doxylamine, ergotamine, fluphenazine, hydroxychloroquine, hydroxyzine, imipramine, meclizine, mesoridazine, methdilazine, methysergide, pheniramine, pyrilamine, tripelennamine, triprolidine, promazlne, and quinidine, and mixtures thereof.

7. A pharmaceutical composition according to Claim 6 wherein said resin particles have an ion-exchange capacity of less than about 6 meq/gram.

8. A pharmaceutical composition according to Claim 7 wherein said pharmacologically-active polyamine drug is selected from chlorpheniramine, doxylamine, and pheniramine.

9. A pharmaceutical composition according to Claim 8 wherein said pharmacologically-active polyamine drug is chlorpheniramine.

10. A pharmaceutical composition according to Claim 9 wherein said resin has bound thereto between about 1.5 equivalents and about 1.7 equivalents of chlorpheniramine per equivalent of cation-exchange capacity.

11. An oral pharmaceutical composition according to Claim 1 wherein said cation-exchange resin further comprises irregularly shaped particles.

12. An oral pharmaceutical composition according to Claim 4 wherein said cation-exchange resin further comprises irregularly shaped particles.

13. An oral pharmaceutical composition according to Claim 6 wherein said cation-exchange resin further comprises irregularly shaped particles.

14. An oral pharmaceutical composition according to Claim 9 wherein said cation-exchange resin further comprises irregularly shaped particles.

15. An oral pharmaceutical composition according to Claim 10 wherein said cation-exchange resin further comprises irregularly shaped particles.

16. An oral pharmaceutical composition according to Claim 1 wherein said cation-exchange resin further comprises regularly shaped particles.

17. An oral pharmaceutical composition according to Claim 4 wherein said cation-exchange resin further comprises regularly shaped particles.

18. An oral pharmaceutical composition according to Claim 6 wherein said cation-exchange resin further comprises regularly shaped particles.

19. An oral pharmaceutical composition according to Claim 9 wherein said cation-exchange resin further comprises regularly shaped particles.

20. An oral pharmaceutical composition according to Claim 10 wherein said cation-exchange resin further comprises regularly shaped particles.