SK59493A3 - Polyamine drug-resin complexes - Google Patents

Description

- 1 · - PI / £ 99-93

Polyamine Drug Complexes with Resin Technique

The present invention describes oral pharmaceutical compositions comprising a pharmaceutically active polyamine new drug linked to a cation exchange resin. The resulting drug-resin complex contains more than one equivalent of amine drug per equivalent of cation exchange resin capacity. The drug-resin complex is optionally coated with a water-permeable diffusion layer, insoluble in fluids, which provides controlled release of the drug under gastrointestinal conditions.

State of the art

Dosage forms with sustained or sustained drug release allow controlled and constant drug delivery. Controlled release of specific drugs has benefits in controlling cough, sleep, enuresis and migraine. This dosage form also allows for controlled release of antimicrobials. Controlled drug release eliminates the need for sleep interruption due to drug uptake, as well as avoiding dose avoidance. Furthermore, it provides the convenience of a single dose of drug per day, which can thus be taken in the morning and the therapeutic level of the drug persists throughout the day.

The controlled drug delivery system delivers. the drug such that its therapeutically effective plasma level remains, noticeably longer than normal for conventional dosage forms.

Uncoated drug release cation exchange resin complexes in the gastrointestinal tract are disclosed in U.S. Pat. U.S. Pat. 4,783,055 and 2,990,332. However, these uncoated complexes provide only a short delay in drug release compared to the composition of the invention and provide only weak drug release control. Management is limited to. changes in particle size and in the crosslinking degree of acidic ionic resins commonly used in. Preparation of adsorption compounds. Various types of coated complexes / drugs with resin have been described in e.g. U.S. Pat. 3,138,525; 3,499,950; a. 3,594,470; Belgian patent no. 729.827; German patent ô. 2,246,037; and Borodkins a. kol. , Journal of Pharmaceutical Science, 60, 1523-1527, 1971), but not. assume that they could be used in the compositions of the present invention, or provide controlled drug release as compositions of the invention.

The present invention discloses controlled-release pharmaceutical compositions obtainable by forming a complex of more than one equivalent of a polyarnine drug b with a pharmaceutically acceptable cation exchange resin and optionally coating the complex with a layer that controls drug diffusion from complex to gastrointestinal fluids.

It is known that pharmaceutically acceptable, dry, non-hydrated forms of resins and their drug complexes will swell (volume up to 60%) upon contact with gastrointestinal fluids.

When the coated resin-drug complex is suspended in an aqueous dosage form, or in contact with gastrointestinal fluids, it expands to its swollen volume to create cracks in the diffusion coating layer. The result is a loss of control of the diffusion of the released drug.

Drug release drugs. for the gastrointestinal tract are described in U.S. Pat. U.S. Pat. Nos. 4,847,077 and 4,221,778, in European Patent Application 254,811 all to Raghunathan; and European Patent Application 254,822 Chow et al. . The methods of preparing the controlled-release products of these publications include three steps: (i) preparing a drug-resin complex; (ii) reacting the complex with a suitable impregnating agent; and (iii) coating the impregnated complex particles with a water-permeable diffusion layer. European Patent Application 249,949 to Sellas'ie et al. three-component coated complexes are described which contain a neutral polymeric binder of hydroxypropylcellulose. A disadvantage of these drug-resin complexes is that impregnation or the presence of a binder is necessary to provide 3 controlled release of the drug upon contact with aqueous fluids of the gastrointestinal tract. In European patent application no. 367,746, Kelleher W.J. et al., issued May 9, 1990, discloses impregnated and non-impregnated drug coating coatings, yet which do not swell, resulting in cracks in the diffusion layer upon contact with aqueous media or gastrointestinal fluids.

The first controlled release drug delivery systems have been targeted at. delaying release or dissolution of the active drug under gastrointestinal conditions. Preliminary testing of these systems was performed in an environment simulating gastric and intestinal fluids, see USP XXII The United States

Pharmacopeia, p. 1788-1789 (1990), as incorporated herein by reference. A second object of interest, upon resolution of the desired release rate, has become the extent or completeness of release or dissolution of the drug over a period of time that would be consistent with the transit time of the digestive tube.

There is a certain category of drugs, the use of which in drug-based drug delivery systems based on ion exchange resin complexes is problematic in view of the latter condition: they are basic drugs containing more than one amino group, the so-called. polyamine drugs. It is characteristic for ion exchange technology that the binding strength of molecules to the ion exchanger increases with increasing number of binding sites in the molecule. A negative consequence of this enhancement is the slow release of the drug molecule bound in two or more sites, under the conditions of the gastrointestinal tract. A clear example is the work of Amsel et al. in Pharmaceutical Technology, April, 1984, p. 28-48, as referred to herein. This paper presents the results of a suspension pharmacokinetic study. which contains coated resin particles with codeine and uncoated resin particles with chloroeniramine. Codeine is monoamine (MW 299 and equivalent 299) and its release to 0.1 N HCl from coated resin particles was adequate. Chlorpheniramine is a diamine (MW 275 and 137.5 equivalent) and its release to 0.1 N HCl was not adequate even when the resin particles were uncoated. In order to achieve a similar release profile of chlorpheniramine as in the case of codeine release in 0.1 N HCl from coated resin particles, it was necessary to create a relatively rough non-physiological environment of 0.4 M KCl. Inadequate dosing of chlorpheniramine is based on the longer time it takes to achieve maximum plasma concentration: 5.9 hours for resin particles over 3.6 hours for drug delivery.

The easiest way to achieve a suitable dose is to add unbound polyamine drugs to the selected dosing farm. An unwanted consequence of the presence of such unbound substance is the unpleasant taste of the composition because many polyarcin drugs; it has a hot unpleasant taste. Another characteristic of ion exchange technology is the equivalent of equivalent to the equivalent, as in the case of acid-base reactions. According to the present invention, the undesirable consequence of this is that, although the amount of bound basic drug with a weight equivalent of only 120 (e.g. pheniramine) is close to 100% of the resin binding capacity, it is an amount insufficient for minimal weight in; in the case of coating the non-impregnated complex with respect to the integrity of the coating.

The present invention solves the above mentioned problems with both the high-tasting and the tasteful dosage in polyamine drug-resin complexes. Notwithstanding theory, it is believed that it is possible to form a drug-resin complex by linking more than one equivalent of drug to a cation exchange resin (i.e., greater than one equivalent of amine per equivalent of cation exchanger). This results in a drug-resin complex that allows both immediate release of the drug present in excess as well as slow or prolonged release of the remainder of the drug. In other words, each molecule of polyarnine drug is bound to the resin by one of its amino groups and therefore occupies only one binding site on the resin. After the formation of a diffuse, water-insoluble coating layer, the resulting coated complex provides a new drug polyarene. with the resin further control over the course of drug release.

According to the present invention, upon introduction of the polyamine drug complex with the resin, into the gastrointestinal fluids (i), a rapid release of that portion of the polyamine drug that is present in an amount above 1 equivalent, (ii) releasing the remainder of the drug at a lower rate, in the form of a long-term dosage, and (iii) releasing the drug in a total amount that is substantially greater than the total amount released from the drug complex with the resin containing one equivalent or less than one drug equivalent per cation exchange capacity equivalent.

It is therefore an object of the present invention to provide a polyamine drug complex with a resin comprising a polyamine drug in an amount exceeding one equivalent of amine per equivalent of cation exchanger capacity that allows controlled release of the drug under gastrointestinal conditions. Further, it is an object of the present invention to provide a polyamine drug complex with a resin comprising a polyamine drug in an amount exceeding one equivalent of amine per equivalent of cation exchange capacity which is optionally coated with a water-permeable diffusion layer insoluble in gastrointestinal fluids and which provides controlled drug release in gastrointestinal conditions. tract. It is a further object of the present invention to provide a polyamine drug-resin complex with improved flavor properties. These and other objects of interest of the present invention will become apparent from the following description.

SUMMARY OF THE INVENTION

The unit dose of the oral pharmaceutical composition comprises polyamine drug complex particles with a 10 to 500 µm resin. These particles contain a pharmacologically active polyamine drug in an amount exceeding one equivalent of amine per equivalent of cation exchanger. This formulation allows controlled release of said active drug. All percentages and ratios herein refer to - ο a. the measurements refer to a temperature of 25 ° C unless otherwise specified.

Describe the invention

&Quot; water-permeable " indicates that the fluids of the digestive tube leak or penetrate the film of the coating layer, and in the latter case, because of its thickness. dissolved or dissolved. permeabi or it or solubility of the selected coating (polymer or mixture of polymers) determines a weaker or stronger dosage such that the drug does not leach out of the complex in an amount exceeding 4% in artificial saliva at 20-40 ° C in 2 minutes.

&Quot; regularly shaped particles " refers to particles whose shape is close to geometric shapes: spherical, elliptical, cylindrical, and. Similarly. These particle shapes are given by geometric principles. Regularly shaped ion exchange resin particles are, for example, Dow XYS-40010.00 (from Dow Chemical Company), which forms a drug-resin complex upon drug binding.

&Quot; irregularly shaped particles " relates to particles whose shape is not as defined above. These are, for example, particles of amorphous shape with an enlarged surface, caused by the presence of the channel ikov or deformations. Irregularly shaped particles of ion exchange resins are, for example, Amberlite IRP-69 (from Rohm and Haas) which, upon drug binding, forms a drug-resin complex.

The abbreviation meq used here denotes 1iekv (y). *

Drugs suitable for use in the present compositions are basic, contain at least two amino groups or substituted amino groups to allow for further bonding. Drug! useful in the present invention are, for example, but not limited to: acetonitrile, amitryptine, bromine eniramine, carbinoxamine, chlorocycline, chlorine, chlorine, clonidine, cyclizine, desipramine, dexbromeniramine, dexchlorin eniramine n, doxylamia, ergotamine, flufenazine, hydroxychlorquine, hydroxyzine, iinipramine, rneclizine, mesoridazine, methdilazine, methysergite, phenirarine, pyrilaraine, tripelenarine n, triprolidines, promazine, quinidine and mixtures thereof.

Ion exchange resins suitable for these formulations are water insoluble, pharmacologically inert, organic or inorganic in nature, contain covalently linked functional groups, ionic or ionizable under suitable pH conditions. The base organic material is or is synthetic (e.g., polymers or copolymers of ascorbic, methacrylic, sultonated styrene, sulfonated divinylbenzene) or partially synthetic (e.g., modified cellulose and dextrans). For example, the basic inorganic mass is silica gel modified by ionic bonding. Covalently bound ionic groups are strongly acidic (e.g., sulionic acid) or weakly acidic (e.g., carboxylic acid). In general, the types of cation exchangers are suitable for use in drug release formulations identical to those used in ion exchange. chromatography and applications such as water deionization. These ion exchangers have been described by H.F. Walton in " Principles of Ion Exchange " (p.312-343) and in " Techniques and Applications of Ion-Exchange Chromatography " (p. 344-361) in Chromatocrraphy, (E.Heitmann, editor), Van Nostrand Reinhold Company, New York (1975), as incorporated herein by reference. The cation exchange resins useful in the present invention preferably have an exchange capacity of less than 6 meq / g, more preferably less than 5.5 meq / g. These cation exchange resins preferably contain covalently bonded strongly acidic ionic groups. The preferred ion exchange particle size is 40 to 150 microns. Particles that are substantially smaller than said lower limit cause difficulty. all preparation steps. Particles that are substantially larger than said upper limit, i. commercially available ion exchange resins of spherical shape up to 1000 microns in diameter are granular in liquid dosage forms and have a high tendency to break during cycles of drying and hydration. In addition, the greater the distance that the replacement ion has to diffuse through these large particles, and the greater the distance that the replaced drug has to diffuse outward from these particles, can be expected to cause a measurable but difficult to control delay in drug release even when uncoated drug-resin complex.

Typical resins useful in the present invention are Amber-lit IRP-69 from Rohm and Haas) and Dow XYS-40010.00 (from The Dow Chemical Company). Both of these resins are sulphonated polystyrene polymers crosslinked with 8% divinylbenzene, with an ion exchange capacity of 4.5 to 5.5 meq / g dry resin in H + form). Basically. differs in shape, Arnberlit IRP-69 consists of irregularly shaped particles that were formed by crushing the corresponding large spherical particles of Arnberlite IRF-120. Dow XYS-40010.00 consists of spherical particles of 45 to 150 microns. Drug binding is possible. performed in a batch process or in a colurnn process, as is conventional in the art. According to one of the typical examples set forth below, the drug-resin complex is prepared at once in a bath. The resulting drug-resin complex is then filtered, washed with ethanol and / or water until complete removal of unbound drug. The complexes are usually air-dried in trays at room temperature. Another possibility of controlled release of drug from the drug-resin complex provides for the introduction of a diffusion coating layer on the particles of these complexes beyond. assuming that the amount of drug in the complex is above the critical value. The coating may be introduced by any technique that results in an adjacent coating on each of the drug-resin complex particles, and where no significant agglomerate particle formation occurs. According to the typical example below, " -coating layers applied in a fluid-bed apparatus with a Wurster configuration.

As the coating material, any of a variety of film-forming agents, or separately, mixtures thereof, or with admixtures of plasticizers, pigments and the like can be used. other substances affecting the properties of the coatings. In general, the main coating components must be water-insoluble but water-permeable. However, it is sometimes desirable to admix a water-soluble substance, such as methylcellulose, to change the permeability of the coating, or to admix an acid insoluble substance but soluble essentially as an enteric coating. Coating materials are. can be introduced as aqueous suspensions or as organic solutions. Suitable examples of coating materials have been described by R.C.Row in Materials used

Q in_Pharmaceutical_Formúlation, (Α.χ. Florence, editor)

Blackwell 1, Scientic Pupl icions, Oxford, 1-36 (1984), as incorporated herein by reference. A water-permeable diffusion layer can be provided. preferably form from substances such as ethylcellulose, methylcellulose and mixtures thereof.

The coated resin drug particles of the present invention are suitable for suspending in an aqueous medium with a single reservation regarding their composition: (i) the absence or only a very small amount of ionic impurities; and (ii.) The limitation of water-miscible organic solvents such as alcohol to a level where there is no further dissolution of the coating diffusion layer. These coated drug-resin particles are also suitable as fillers in capsules for dispensing in solid form.

Test method

Moisture determination was performed in the Mettler LP 16 infrared heating system on PE160 balances. Due to the varying moisture content over relatively short time intervals, moisture was always determined just prior to the use of the resin or drug complex with the resin. Corrections were calculated for the current quantities, therefore all values are related to dry weight.

Immediately after completion of the preparations, all drug-resin complexes were washed with a suitable solvent until complete removal of unbound drug. Where salts were used in the binding mixture, the complexes were washed with water. Where the free base form of the drug was used in the binding mixture, the complexes were washed with ethanol. Further washing was continued in the bath or in the percolator until spectrophotometric measurement showed that the supernatant no longer contained any unbound drug. All complexes were analyzed for drug content. A precisely weighed (about 500 mg) sample of the complex was placed in a 200 mL titration flask containing 100 mL of 0.5 M sodium acetate in 90% ethanol and refluxed for one hour. Then the mixture was cooled to room temperature and diluted with 200 mL of 10 ethanol. An aliquot was removed from the clear supernatant after settling or centering. By appropriate dilution, the drug content in the supernatant was determined spectrophotometrically. The drug content of the complex is expressed as a percentage by weight, relative to the drug in the free base, unless otherwise indicated.

Determination of drug release of drug-resin complex was carried out in an apparatus corresponding to the dissolution apparatus 2, USP. In all cases, a stirrer with two blades with a rotational speed b r rn was used. The drug release medium had a composition of 900 mL of 0.1 N HCl or 0.1 N HCl transferred in situ to. 0.07 M sodium phosphate buffer (pH 7.2) by adding 24.8 g sodium phosphate dodecahydrate to 900 mL 0.1 N HCl. The ambient temperature was maintained at 37 ° C. The drug complex of the resin was added in an appropriate amount to provide the following doses (related to the commonly administered forms): doxylarine succinate, 15 µm; chloropheniramine maleate, 16 mg; pheniramine maleate, z 5 mg. Resin drug complexes were added to the release medium as powders. Approximately 10 ml of sample from the reaction vessel was collected at appropriate time intervals and pre-primed with a syringe equipped with a filter. Exactly 5.0 ml of the filtrate was stored for further analysis. The residue of the filtrate was returned to the reaction vessel. The drug-resin complex particles attached to the filters were rinsed into the reaction vessel with exactly 5.0 mL of fresh release solution. The absorbance of the filtrate samples was measured at. the ultraviolet spectrum peak wavelength on the spectrophotometer Perl-Elrner 55 > 2 or Larnbda 3B UV / VIS. The absorbance values were expressed as percent of drug release. According to an alternative procedure, the samples were analyzed by HPLC on a reverse phase phenyl column, eluting with methanol water: acid. acetic (60: 40: 2 v / v, 5mM sodium hexanesulphonate), equipped with a Waters 6000A pump and a variable wavelength variable 450 spectrophotometric detector; measurements were made at the maximum absorbance wavelength. Peak areas were expressed as percent of drug release. The diffusion coating layers were applied by the fluid bed method using a Glatt CPCG-5 type Wuster. The conditions of a typical coating process were as follows: temperature, incoming air 7 ° C; 60 psi air atomizing pressure; spraying rate 20 to 25 g / roiri; outgoing air temperature 40 to 50 ° C. Microscopic testing of the coated particles was carried out using a transmission and stereoselective microscope. The size of the coating on the drug-resin complex particles was determined by removing the coating layer with a suitable solvent and weighing the dry residue after evaporation of the solvent. A precisely weighed about 2.0 g sample of coated drug-resin complex was placed in a 30 ml glass centrifuge tube. Ethanol (20 mL) was added and the mixture occasionally stirred for 30 min. Then the mixture was centered and decanted three times in succession. The combined ethanol extracts were evaporated to dryness using a vacuum evaporator. The dry residue flask was rinsed four times with several millimeter volumes of methyl chloride / acetone (9: 1 by volume). The rinsing solutions were transferred to a tared aluminum dish and evaporated in a fume hood. Then the dish was heated to 50 ° C for 30 minutes and weighed after cooling. The weight gain of the tared dish was the weight of the ethylcellulose coating. The resulting values correspond very well to the amount of coating applied in the coating apparatus by the fluidized bed method.

The following examples illustrate the benefits of the present invention and include combinations of both essential and optional ingredients. -12 " .Λ. *

Examples of wyna ya-y

EXAMPLE I

This example describes the preparation of a drug-resin complex containing doxylamine bound to an Amberlite IHP-69 type resin. This complex contains 1-92 equivalents of doxylamine per equivalent of drug from the complex in P fluid compared to the complex containing the cation exchange capacity. He experienced the release of conditions simulating the gastric gastric behavior profile of doxylamine most as one drug equivalent per cation exchanger capacity equivalent under the same conditions. (A). Preparation of a complex of doxylamine with Amberlite IRP-69 containing 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 was placed in a round flask equipped with a condenser, containing 50 ml of water pre-heated. 100 ° C. Further, doxylamine (free base) s was added. the mixture was kept at 100 ° C with stirring for 2 hours. Then, the mixture was filtered and the obtained drug cake resin resin cake was washed with ethanol until absorbed at 261 nm. The drug complex with Resin, now free of unbound drug, was dried at room temperature. According to the analysis, this complex contained 57.0% by weight of doxylamine. (B). Preparation of a complex of doxylamine with Amberlite IRP-69 containing 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 was placed in a round flask containing 20 mL of water preheated to 60 ° C. Next, doxylamine succinate was added and the mixture was kept at 60 ° C with stirring for 2 hours. Then the mixture was filtered and the obtained drug cake resin resin cake was washed with water until absorbed 13 of the filtrate at 261 nm. The drug-resin complex, now free of unbound drug, was dried at room temperature. According to the analysis, this complex contained 40.2% by weight of carboxylate. (C). The complexes prepared according to procedures (A) and (B) gave the following doxylarine release profile in the reaction of 0.1 N HCl (simulating gastric fluid environment) The release of doxylarine from complex (A) is significantly higher than in case (B) '. % of released doxylarine in 0.1 N HCl time (minutes) 15 30 60 120 180 complex (A) 68 69 68 68 complex (B) 41 48 49

EXAMPLE II

This example describes the preparation of a drug complex with a resin containing pheniramine bound to an Amberlite IRP-69 resin. This complex contains 1/92 equivalents of pheniramine per equivalent of cation exchange capacity. The drug release profile from the complex under gastric fluid simulating conditions is compared to the behavior profile of the pheniramine complex containing less than one drug equivalent per cation exchanger capacity under the same conditions. '(A). Preparation of pheniramine-Amberlite IRP-69 complex containing 1.92 equivalents of pheniramine per equivalent of cation exchange capacity.

Amberlite IRP-69 (H ··-form) 0.500 g

Doxylamine (free base) 0.632 g The resin was placed in a round flask equipped with a condenser, stirring for a month containing 25 ml of water preheated to 100 ° C. Thereafter, pheniramine (free base) was added and the mixture was maintained at 100 ° C with stirring for 3 hours. Thereafter, 14 was filtered out and the obtained drug-cake resin cake was washed with ethanol until the filtrate absorbed at 2G0 nm. The drug-resin complex, now free of unbound drug, was dried at room temperature. According to the analysis, this complex contained 54.2% by weight of keriramine. . (B). Preparation of the pheniramine complex with Arnberlit IEP-69 containing 0.91 equivalents of pheniramine per equivalent of cation exchange capacity.

Amberlite IEP-69 (H + -alcohol) 1,000 g

Pheniramine maleate 0.927 g The resin was placed in a round flask containing 10 ml of water preheated to 60 ° C. Further, pheniramine maleate was added and the mixture was maintained at 60 ° C with stirring for 3 hours. Then the mixture was filtered. and the obtained drug cake resin resin cake was washed with water until the filtrate absorbed at 260 nm. The resin complex, now free of unbound drug, was dried at room temperature. According to the analysis, this complex contained 35.9% by weight of pheniramine. (C). The complexes prepared according to procedures (A) and (B) gave the following pheniramine release profile in reaction with 0.1 N HCl (simulating gastric fluid environment). The release of pheniramine from complex (A) is significantly higher than that of (B). % liberated of pheniramine in 0.1 N HCl time (minutes) com x (A) complex (B) 15 6 9 35 30 69 37. EXAMPLE III This example describes the preparation of a drug complex with a chlorine containing resin. bound to resin type 15 resin

Amberlite IRP-69 and the effect of subsequent coating of the complex with a diffusion coating. These complexes (coated and uncoated) contain 1.72 equivalents of chlorpheniramine per equivalent of cation exchange capacity. Drug release profiles from complexes under gastric fluid simulation conditions are compared to the behavioral profiles of pheniramine complexes (both coated and uncoated) that contain less than one equivalent of drug per equivalent of cation exchange capacity under the same conditions. (A). Preparation of the chloropheniranine complex with IRber-IRP-69 containing 1.72 equivalents of chlorpheniramine per equivalent of cation exchange capacity.

Amberlite IRP-69 (H + -form) 1250 g

Chlorpheniramine (free base) 1759 g The resin was charged to a 70 L round bottom flask containing 15 L of water preheated to 70 ° C. Further, chloroeniramine (free base) was added and the blend was maintained at 85 ° C with stirring for 1 hour. Then the contents of the flask were transferred to 20 L of polyethylene bucket and left at room temperature until the majority of the complex settled. The liquid supernatant containing the suspended fine particles was decanted and removed. The settled Dol complex is diluted with 2.5 liters of ethanol and the resulting slurry is filtered 1 · The obtained n · v · w complex cake is obtained. ,. in ethanol (4.5 L) until the drug with P1SI1 > Λ y, i j. in , . mp at 264 nm. Absorbable Absorbent Drug Complex 1. . The mixture was stirred at room temperature and the complex contained 54.7% by temperature. According to the analysis of chlorpheniramine ·, “,. Chloroform eniramine with Årnberlit (B). Coating of the above process (A). 'IRP-69 prepared by' 'V " ,, with ftmberlite IRP-69 1000 g 100 cr 1900 g mixing in preheated Kóp lex Chlorine

Ethylcellulose, M-10 Ethyl acetate

Ethyl cellulose was present in,,. "",. the resin was placed with ethyl acetate. Complex with i1 *., U. __ - even in the fluidized bed and aerated by the incoming air coater ^ quot " The 7 + C solution was sprayed at a rate of 30 ** 25? / min in a total of 2000 g. Preheated air aeration was continued for 2 minutes after the coating solution was finished. (C). Preparation of the chlorpheniramine-Amberlite IRP-69 complex containing 0.92 equivalents of chlorpheniramine per equivalent of cation exchange capacity.

Amberlite IRP-69 (H + -form) 1500 g '· Chloropheniramine maleic acid, 1495 g The resin was charged to a 70 L round-bottomed flask containing 15 L of water preheated to 60 ° C. Further, chloroeniramine (free base) and a mixture of buff was added. maintained at 60 ° C with stirring for 1 hour. Then the contents of the flask were transferred to 20 L of polyethylene bucket and left at room temperature until the majority of the complex settled. The liquid supernatant containing the suspended fine particles was decanted and discarded. The settled complex was diluted with 3.0 L of ethanol and the resulting slurry filtered. The obtained filter cake of the drug-resin complex was washed with water (3 x 1 L) and 5 L of ethanol until the absorbent absorbance of the filtrate at 264 nm. The drug-resin complex was spread and dried at room temperature. According to the analysis, this complex contained 39.2% by weight of chloroeniramine. (D). Coating of the chlorisiniramine-Amberlite IRP-69 complex prepared as described above (C).

Chlorpheniramine-Amberlite IRP-69 1000 g complex

Ethyl cellulose, N-10 100 g

Ethyl acetate 1900 g

Ethyl cellulose was dissolved in ethyl acetate with stirring. The resin complex was placed in a preheated fluidized bed coating apparatus and aerated with 70 ° C heated inlet air. The coating solution was sprayed at a rate of 20 and 25 g / rain in a total of 2000 g. Preheated air aeration was continued for 2 minutes after the coating solution was finished. (E). The complexes prepared according to procedures (A), (B), (C) and (D) gave the following chlorpheniramine release profile in reaction with 0.1 N HCl (simulating gastric fluid environment). The release of chlorpheniramine from the uncoated complex (A) is significantly higher than that of the uncoated 17 complex (C). The uncoated complex (A) can be successfully obtained by a diffusion coating layer, resulting in a sustained release of the drug as a coated complex (B). % chlorpheniramine released in 0.1 N HCl time complex (A) complex (B) complex (C) complex (D) (minutes) (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 describes the preparation of a drug-resin complex containing chloropheniramine bound to a Dow XYS resin and the determination of sequential release of chlorpheniramine under conditions simulating gastric fluids and at pH 7.2 (A) Preparation of chlorophenirane complex with Dow XYS "containing 1.56 equivalents of chlorpheniramine per equivalent of cation exchange capacity.

Dow XYS 400100.00. (H + -form) 5,000 g

Chlorine eniramine (free base) 7.227 g in resin was charged to a round flask equipped with a condenser containing 50 ml of water preheated to 100 ° C. Further, chloropheniramine (free base) was added and the mixture was added. maintained at 100 ° C with stirring for 2 hours. Thereafter, the filter cake was filtered and the drug cake resin cake obtained was washed with ethanol until the absorbance of the filtrate was absorbed at 264 nm. The drug-resin complex, now free of unbound drug, was dried at room temperature. According to the analysis, this complex contained 53.0% by weight of chlorpheniramine. (B). The complex prepared according to procedure (A) gave the following release profile. chloropheniramine. Release was accomplished by reaction with 0.1 N HCl (simulating gastric fluid environment) for 60 minutes and in pH 7.2 phosphate buffer for 60 minutes. The release of chlorpheniramine in a stomach-simulating environment during the first 60 minutes was similar to the drug release patterns of Examples I (A), II (A) and III (A). Changing the pH to 7.2 resulted in complete release of the bound Schlfenpheniramine. % released chlorpheniramine time (minutes) complex (A) • (0.1 M HCl) 60 68 15 30 60 ť pH 7.2 phosphate solution) 75 90 90 98 120 103

Claims (14)

YPATE-T Ο VE 1. Oral pharmaceutical preparation, comprising cationic resin particles of 10 to 500 microns in one dose containing bound pharmacologically active polyamine drug. in an amount exceeding one equivalent of amine per equivalent of cation exchange capacity, and said composition provides controlled release of the active drug. 2. A pharmaceutical having 150 microns. 3. Pharmaceutical 80 microns. 4. A pharmaceutical composition as claimed in claim 1 wherein the particle size is 35 to the composition of claim 2, wherein the particle size is 40 to the composition of claim 3, a =. wherein said drug-resin complexes further comprise a water-permeable diffusion coating layer in an amount of 1.5 to 25% by weight based on the weight of the drug complex, with the resin. 5. A pharmaceutical composition according to claim 4 wherein said water-permeable diffusion coating is derived from the group consisting of ethylcellulose, methylcellulose and mixtures thereof. 5. 'Pharmaceutical composition according to. 3. The method of claim 5, wherein said pharmacologically active polyamine drug is derived. from the group consisting of acetic acid, amitryptyline, bromine eniramine, carbinoxamine, chlorocyclizine, chlorpheniramine, chlorpromazine, clonidine, cyclizine, desipramine, dexbrompheniramine, dexchloropheniramine, doxylamine, ergotamine, fufenazine, hydroxy chloroquine, hydroxyzine, imipramine, meclizine, hydroxyzine, imipramine, meclizine, mesoridazine, methdilazine, methysergite, pheniramine, pyrimidine, tripelenamine, triprolidine, promazine, quinidine, and mixtures thereof. 7. Pharmaceutical composition according to. 3. The method of claim 7 wherein the cation exchange capacity of said resin particles is less than about 6 meq / g. 20 20 Q. Pharmaceutical characterized polyamine drug Jerolin. 9. A pharmaceutical composition characterized in that the polyamine drug is chlorophenamine. A pharmaceutical composition characterized by the composition of claim 7, wherein said composition is a composition according to claim 7. and pharmacologically active is chlorpheniramine, doxylamine or according to claim 8, that pharmacologically active according to claim 9, on said resin is bound 1.5 to 1.7 equivalents of chlorpheniramine per equivalent of cation exchanger 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. An oral pharmaceutical composition according to claim 6, wherein said cation exchange resin further comprises irregularly shaped particles. 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. 15. An oral pharmaceutical composition according to claim 1 wherein said cation exchange resin further comprises regularly shaped particles. An oral pharmaceutical composition according to claim 4, characterized in in that said cation exchange. the resin further comprises regularly shaped particles. An oral pharmaceutical composition according to claim 6, wherein said cation exchange resin further comprises regularly shaped particles. An oral pharmaceutical composition according to claim 9, wherein said cation exchange resin further comprises regularly shaped particles. - 21 - 20. An oral pharmaceutical composition according to claim 10, wherein said cation exchange resin further comprises regularly shaped particles.