Method for obtaining a Stabilized controlled release formulations having acrylic polymer coating

Abstract: A stabilized solid controlled release dosage form having a coating derived from an aqueous dispersion of an acrylic polymer is obtained by overcoating a substrate including a therapeutically active with an aqueous dispersion of the plasticized acrylic polymer and then curing the coated substrate at a temperature above the glass transition temperature of the plasticized acrylic polymer, until the coated dosage form attains a stabilized dissolution profile substantially unaffected by exposure to storage conditions of elevated temperature and/or elevated relative humidity.

Description: BACKGROUND OF THE INVENTION An important aspect of all forms of low dosage forms is related to the stability of the same. The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment. Stability study requirements are covered, e.g., in the Good Manufacturing Practices (GMPs), the U.S.P., as well as in New Drug Applications (NDAs) and Investigational New Drug Applications (INDs). The ingredients used in sustained release dosage formulations often present special problems with regard to their physical stability during storage. For example, waxes which have been used in such formulations are known to undergo physical alterations on prolonged standing, thus precautions are taken to stabilize them at the time of manufacture or to prevent the change from occurring. Fats and waxy materials when used in purified states are known to crystallize in unstable forms, causing unpredictable variations in availability rates during stability testing at the time of manufacture and during later storage. It is known that certain strategies can be undertaken to obtain stabilized controlled release formulations in many cases, such as insuring that the individual ingredients are in a stable form before they are incorporated into the product, and that processing does not change this condition, retarding the instability by including additional additives, and inducing the individual ingredients of the dosage form to reach a stable state before the product is finally completed. It is also recognized that the moisture content of the product can also influence the stability of the product. Changes in the hydration level of a polymeric film, such as the ethyl celluloses, can alter the rate of water permeation and drug availability. Also, binders such as acacia are known to become less soluble when exposed to moisture and heat. However, moisture content of a product can be controlled fairly successfully by controls in the processing method and proper packaging of the product. Hydrophobic polymers such as certain cellulose derivatives, zein, acrylic resins, waxes, higher aliphatic alcohols, and polylactic and polyglycolic acids have been used in the prior art to develop controlled release dosage forms. Methods of using these polymers to develop controlled release dosage forms such as tablets, capsules, suppositories, spheroids, beads or microspheres are to overcoat the individual dosage units with these hydrophobic polymers. It is known in the prior art that these hydrophobic coatings can be applied either from a solution, suspension or dry. Since most of these polymers have a low solubility in water, they are usually applied by dissolving the polymer in an organic solvent and spraying the solution onto the individual drug forms (such as beads or tablets) and evaporating off the solvent. Aqueous dispersions of hydrophobic polymers have been used in the prior art to coat pharmaceutical dosage forms for aesthetic reasons such as film coating tablets or beads or for taste-masking. However, these dosage forms are used for immediate release administration of the active drug contained in the dosage form. Attempts to prepare stable controlled release pharmaceutical formulations using aqueous dispersions of hydrophobic polymers have been unsuccessful due to stability problems. Therefore, it is desirable to prepare a controlled release formulation prepared from an agueous dispersion of a hydrophobic polymer. However, to date, attempts to prepare stable controlled release pharmaceutical formulations using agueous dispersions of hydrophobic polymers have been unsuccessful due to stability problems. GB- A 2 178 313 relates to an improved granular delayed-release form of pharmaceutically active substances. The delayed-release forms are prepared by coating a granulated and/or crystalline pharmaceutically active substance with a coating material mixture consisting of a homogeneous mixture of a poly(H + meth)-acrylic acid-(methyl + ethyl) ester which is insoluble but dispersible in water and an ethyl cellulose which is insoluble but dispersible in water in the weight ratio of 20:1 to 1:5. The coated granules are then heated for at least 5 minutes at elevated temperatures ranging from between 50° to 120°C. The coating does not essentially consist of ammonium methacrylate copolymers and said coating does not comprise plasticizers. Further, the teaching of GB-A 2 178 313 does not relate to a heat treatment for at least 24 hours and up to a predetermined endpoint. EP-A 0 463 877 relates to a controlled release pharmaceutical preparation comprising a core containing a medicinal compound and a coating layer containing a higher fatty salt and a water-insoluble and slightly water-permeable acrylic polymer having a trimethyl ammonium ethyl group. Apart from the drying and curing treatment, the EP-A 0 463 877 does not relate to a heat pretreatment to stabilize the coating dissolution profile. EP-A 0 377 518 discloses a sustained release pharmaceutical pellet composition suitable for treating pain-associated conditions, which comprises a core element including at least one active ingredient of high solubility and a core coating for the core element which is partially soluble at a highly acidic pH to provide a slow rate of release of active ingredient. The coating disclosed in EP-A 0 377 518 comprises a plasticizer combined with a methacrylic acid/acrylic acid ethyl ester 1:1 copolymer. There is no heat treatment of the coated composition disclosed, other than the usual drying step. In particular, when coating these pharmaceutical forms using agueous polymeric dispersions to obtain a desired release profile of the active drug(s) over several hours or longer, it is known in the art that the dissolution release profile changes on ageing. This was recently demonstrated by Munday, et al., Drug Devel. and Indus. Phar., 17 (15) 2135-2143 (1991), which reported the effect of storing theophylline mini-tablets film coated with ethyl cellulose with PEG (2:1 ratio; total coating = 3% w/w), ethyl cellulose with Eudragit ® L (2:1 ratio; total coating = 3% w/w); and Eudragit ® RL (amount of coating a 1.5% w/w) at varying temperatures and relative humidities upon the rate of drug release. Samples were subjected to isothermal storage at 28°C. 35°C and 45°C with the relative humidity (RH) maintained between 55-60%, under cyclic conditions of 45°C at 55% RH for 24 hours, then at 28°C and 20% RH for 24 hours, and then at 5°C and 10% RH for 24 hours, after which the cycle was repeated, and alternating conditions every 24 hours between 45°C and 55% RH and 28°C and 0% RH. The aging process brought about by storage under the above stress conditions impeded dissolution, irrespective of the nature of the polymeric film. The greatest reduction in release rate was said to occur in the first 21 days (isothermal storage) after coating. This instability problem is known to not exist when the polymers are applied from organic solvent solution. The use of organic solvents in the preparation of polymer coatings is considered problematic as the formulations have inherent problems with regard to flammability, carcinogenicity, environmental concerns, and safety in general. Furthermore, attempts to prepare controlled release pharmaceutical formulations using organic coatings have been largely unsuccessful due to stability problems, the rate of drug release being changed upon storage. For example, it has been considered desirable in the art to prepare a controlled release formulation which utilizes a retardant coating derived from an aqueous acrylic polymer dispersion, such as Eudragit ® , commercially available from Rohm Pharma. However, to date it has not been possible to obtain a controlled release formulation which is stable under various storage conditions. More particularly, it is known that a controlled release coating comprising Eudragit ® is not stable when cured according to recommended curing conditions by the manufacturer of 45°C for 2 hours. OBJECTS AND SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a controlled release dosage form for oral administration which has a controlled release coating derived from an aqueous acrylic polymer dispersion, such that an essentially stabile dissolution profile of medicament is obtained under various storage conditions. It is a further object of the present invention to provide a controlled release dosage form prepared with an overcoat derived from an aqueous dispersion of an acrylic resin which is stable under stressed conditions, including extended periods of high temperature and high humidity. These objects and others have been accomplished by the present invention, which relates to a method for obtaining, a solid dosage form according to claim 1 which has a controlled release overcoat derived from an aqueous dispersion of an acrylic resin which provides a substantially stable release pattern of a therapeutically active agent(s) contained therein. The present invention further relates to the surprising discovery that when the coated formulation is exposed to certain elevated or "stressed" conditions of temperature for a certain amount of time, a desired endpoint may be attained whereat the release rate of the therapeutically active agent does not substantially change upon ageing under a wide range of temperature and humidity conditions. This surprising discovery makes it possible to the controlled release coatings of the present invention for a variety of pharmaceutical dosage forms to produce stable controlled release pharmaceutical products. The present invention is also related to a method for obtaining a stabilized controlled release formulation comprising beads coated with a plasticized acrylic polymer as described in claim 1. In a further embodiment, the method further includes the step of determining the endpoint for a particular formulation by exposing the formulation to various stages of the above-mentioned curing and obtaining dissolution profiles for the formulation until the dissolution profiles of the formulation are substantially stabilized. The formulation is then modified, if necessary, to obtain a desired dissolution profile of the therapeutically active agent based on the end point. The present invention is as defined by the appended claims. DETAILED DESCRIPTION In the embodiments of the present invention, the acrylic polymer comprising the controlled release coating is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In order to obtain a controlled release formulation, it is usually necessary to overcoat the beads comprising the therapeutically active agent with a sufficient amount of the aqueous dispersion of acrylic polymer to obtain a weight gain level from about 5 to about 15 percent, although the overcoat may be lesser or greater depending upon the physical properties of the therapeutically active agent and the desired release rate, the inclusion of plasticizer in the aqueous dispersion of acrylic polymer the manner of incorporation of the same, for example. An example of a suitable controlled release formulation pursuant to the present invention will provide a dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C, is between 12.5 and 42.5% (by wt) therapeutically active agent released after 1 hour, between 25 and 55% (by wt) released after 2 hours, between 45 and 75% (by wt) released after 4 hours and greater than about 55% (by wt) released after 6 hours. This example is, of course, not intended to be limiting in any manner whatsoever. In order to obtain a desirable dissolution profile for a given therapeutically active agent, such as that detailed above, it may be necessary to incorporate two or more ammonio methacrylate copolymers having differing physical properties. For example, it is known that by changing the molar ratio of the quaternary ammonium groups to the neutral (meth)acrylic esters, the permeability properties of the resultant coating can be modified. In a preferred embodiment of the present invention, the acrylic coating is derived from a mixture of two acrylic resin lacquers used in the form of aqueous dispersions, commercially available from Rohm Pharma under the Tradename Eudragit ® RL 30 D and Eudragit ® RS 30 D, respectively. Eudragit ® RL 30 D and Eudragit ® RS 30 D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit ® RL 30 D and 1:40 in Eudragit® RS 30 D. The mean molecular weight is about 150.000. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. Eudragit ® RURS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids. The Eudragit ® RURS dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a controlled release formulation having a desirable dissolution profile. Desirable controlled release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit ® RL, 50% Eudragit® RL and 50% Eudragit ® RS, and 10% Eudragit ® RL:Eudragit ® 90% RS. In addition to modifying the dissolution profile by altering the relative amounts of different acrylic resin lacquers, the dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating. The aqueous dispersions of acrylic polymers used as coatings in the present invention may be used in conjunction with spheroids (or beads) in order to obtain a desired controlled release of the therapeutically active agent. Beads prepared in accordance with the present invention can be presented in a capsule or in any other suitable dosage form. The coating formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free. It is preferred that the acrylic coatings used in the present invention include an effective amount of a suitable plasticizing agent, as it has been found that the use of a plasticizer will further improve the physical properties of the film. For example, the use of a plasticizer may improve the film elasticity and lower the film-forming temperature of the dispersion. The plasticization of the acrylic resin may be accomplished either by so-called internal plasticization" and "external plasticization." Internal plasticization usually pertains directly to molecular modifications of the polymer during its manufacture, e.g., by copolymerization, such as altering and/or substituting functional groups, controlling the number of side chains, or controlling the length of the polymer. Such techniques are usually not performed by the formulator of the coating solution. External plasticization involves the addition of a material to a film solution so that the requisite changes in film properties of the dry film can be achieved. The suitability of a plasticizer depends on its affinity or solvating power for the polymer and its effectiveness at interfering with polymer-polymer attachments. Such activity imparts the desired flexibility by relieving molecular rigidity. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application. Most preferably, about 20% plasticizer is included in the aqueous dispersion of acrylic polymer. An important parameter in the determination of a suitable plasticizer for a polymer is related to the glass transition temperature (Tg) of the polymer. The glass transition temperature is related to the temperature or temperature range where there is a fundamental change in the physical properties of the polymer. This change does not reflect a change in state, but rather a change in the macromolecular mobility of the polymer. Below the Tg, the polymer chain mobility is severely restricted. Thus, for a given polymer, if its Tg is above room temperature, the polymer will behave as a glass, being hard, non-pliable and rather brittle, properties which could be somewhat restrictive in film coating since the coated dosage form may be subjected to a certain amount of external stress. Incorporation of suitable plasticizers into the polymer matrix effectively reduces the Tg, so that under ambient conditions the films are softer, more pliable and often stronger, and thus better able to resist mechanical stress. Other aspects of suitable plasticizers include the ability of the plasticizer to act as a good "swelling agent" for the acrylics, and the insolubility of the plasticizer in water. Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit® RURS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin. Triethyl citrate is an especially preferred plasticiser for the aqueous dispersions of acrylics of the present invention. It has further been found that the addition of a small amount of talc reduces the tendency of the aqueous dispersion to stick during processing, and acts as a polishing agent. The stabilized controlled release formulations obtained by the method of the present invention slowly release the therapeutically active agent, e.g.. when ingested and exposed to gastric fluids. The controlled release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating, altering the manner in which the plasticizer is added, by varying the amount of plasticizer relative to acrylic resin, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc. A wide variety of therapeutically active agents can be used in conjunction with the present invention. The therapeutically active agents (e.g. pharmaceutical agents) which may be used in the compositions of the present invention include both water soluble and water insoluble drugs. Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.), anti-inflammatory agents (e.g.. naproxyn, diclofenac, indomethacin, ibuprofen, acetaminophen, aspirin, sulindac), gastro-intestinals and anti-emetics (e.g., metoclopramide), anti-epileptics (e.g., phenytoin, meprobamate and nitrezepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-lussive agents and expectorants (e.g., codeine phosphate), anti-asthmatics (e.g. theophylline), antispasmodics (e.g. atropine, scopolamine), hormones (e.g., insulin, leparin), diuretics (e.g., eltacrymic acid, bendrofluazide), anti-hypotensives (e.g., propranolol, clonidine), bronchodilators (e.g., albuterol), anti-inflammatory steroids (e.g.. hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, antacids, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine). The above list is not meant to be exclusive. In certain preferred embodiments, the therapeutically active agent comprises hydromorphone, oxycodone, dihydrocodeine, codeine, hydromorphone, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing. and mixtures of any of the foregoing, and the like. In other preferred embodiments, the therapeutically active agent comprises theophylline. When the dispersion of acrylic resin is used to coat inert pharmaceutical beads such as nu pariel 18/20 beads (sugar spheres, commercially available from Ingredient Tech. Corp.), a plurality of the resultant stabilized solid controlled release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by gastric fluid, In this embodiment, beads coated with a therapeutically active agent are prepared, e.g. by dissolving the therapeutically active agent in water and then spraying the solution onto beads for example, nu pariel 18/20 beads, using a Wurster insert. Optionally, additional ingredients are also added prior to coating the beads in order to assist the hydromorphone binding to the beads, and/or to color the solution, etc. For example, a product which includes hydroxypropyl methylcellulose, etc. with or without colorant may be added to the solution and the solution mixed (e.g., for about 1 hour) prior to application of the same onto the beads. The resultant coated beads, may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the acrylic coating. An example of a suitable barrier agent is one which comprises hydroxypropyl methylcellulose. However, any film-former known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product. The hydromorphone, HPMC protected (optional) beads may then be overcoated with the acrylic polymer. The dispersion of acrylic polymer preferably further includes an effective amount of plasticizer, e.g. triethyl citrate. Pre-formulated dispersions of acrylic resins, such as various commercially available forms of Eudragit®, such as Eudragit® RS30D and Eudragit® RL 30D, may be used. The coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction. Color may be added to the solution of the therapeutically active agent instead, or in addition to the overcoat Suitable ingredients for providing color to the formulation include titanium dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, may, however, increase the retard effect of the coating. Alternatively, any suitable method of providing color to the formutations of the present invention may be used. The plasticized coating of acrylic polymer may be applied onto the beads comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art. In a preferred method, a Wurster fluidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on. A sufficient amount of the coating to obtain a predetermined controlled release of the therapeutically active agent when said coated beads are exposed to aqueous solutions, e.g. gastric fluid, is preferably applied, taking into account the physical characteristics of the therapeutically active agent, the manner of incorporation of the plasticizer, etc. After coating with acrylic resin, a further overcoat of a film-former, such as Opadry® (a product commercially aviable from Coloron, West Point, Pennsylvania, which contains hydroxypropyl methyl cellulose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol and D&C Red No. 30 Aluminium Lake), is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads. Next, the coated beads are cured in order to obtain a stabilized release rate of the therapeutically active agent. Traditionally, curing has been carried out for Eudragit® coated formulations, if at all, via a fluid bed at 45°C for 2 hours after application. Such a standard curing is recommended by Rohm Pharma because it is above the glass transition temperature (Tg) of Eudragit® RS 30 D plasticized with triethylcitrate at a 20% level of solids. This recommended curing does not stabilize the dissolution profile of the formulation upon storage, as will be demonstrated by the examples set forth herein. The curing of the coated beads pursuant to the present invention is effected by subjecting the coated beads to a temperature greater than the Tg of the coating formulation and continuing the curing until an endpoint is reached at which the coated formulation attains a dissolution profile which is substantially unaffected by exposure to storage conditions of elevated temperature and humidity. The curing time is at least 24 hours, and the curing temperature is about 45°C. It has further been discovered in the present invention that it is not necessary to subject the coated beads to humidity levels above ambient conditions during the curing step in order to achieve a stabilized end product. One possible mechanism for the change in the dissolution profile of prior art products cured by the standard methods is that these products continue to cure during storage, and may never reach a stabilized end-point at which the product provides a substantially constant dissolution profile. In contrast, the cured products of the present invention provide a release rate of the therapeutically active agent which is substantially unaffected during storage by elevations in temperature and humidity. In preferred embodiments of the present invention, the stabilized product is obtained by subjecting the coated beads to oven curing at a temperature above the Tg of the plasticized acrylic polymer for the required time period, the optimum values for temperature and time for the particular formulation being determined experimentally. In certain embodiments of the present invention, the stabilized product is obtained via an oven curing conducted at a temperature of about 45°C for a time period from about 24 to about 48 hours. Thus, in certain embodiments, it may be preferable to cure the product for, e.g., 36 hours. In certain preferred embodiments, the product is cured for about 48 hours. It is also contemplated herein that certain products coated with the controlled release coating of the present invention may require a curing time longer than 48 hours, e.g. 60 hours or more. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever. Example 1 (Comparative) Preparation of Hydromorphone Beads Hydromorphone (which is 4,5-Epoxy-3-hydroxy-N-methyl-6-oxomorphinan) beads were prepared by dissolving hydromorphone HCl in water, adding Opadry® Y-5-1442, light pink (a product commercially available from Coloron, West Point. Pennsylvania, which contains hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol and D&C Red No. 30 Aluminum Lake). 20% w/w, and mixing for about 1 hour, and then spraying onto nu pariel 18/20 beads using a Wurster insert. The resultant preparation had the formula set forth in Table 1 below: TABLE 1 Ingredients Percent (by wt) Amt/Unit (mg) Hydromorphone HCl 5.0% 4.0 mg Nu Pariel 18/20 92.5% 74.0 mg Opadry® Lt. Pink Y-5-1442 2.5% 2.0 mg 100.0% 80.0 mg EXAMPLE 2 (Comparative) Retardant Coating - No Curing Step In Example 2, hydromorphone beads prepared in accordance with Example 1 were overcoated with Eudragit® RS 30D to a 5% weight gain as set forth in Table 2 below. Citroflex ® (a product commercially available from Moroflex, North Carolina which contains citrate esters) is used as plastiziser. No terminal drying was conducted. TABLE 2 Ingredients Percent (by wt) Amt/Unit (mg) Hydromorphone beads 92.59 80 Eudragit ® RS30D 4.63 4 Citroflex 2 (triethyl citrate) 0.93 0.8 Talc 1.85 1.6 Purified water qs 100 86.4 The hydromorphone beads were tested for initial dissolution, and then stored for one month under accelerated conditions of 37°C/80%RH (RH = relative humidity). After one month, the beads were found to have agglomerated. Dissolution tests were carried out via the USD Basket Method, 37°C, 100 RPM, first hour 700 ml gastric fluid at pH 1.2, then changed to 900 ml at 7.5. The dissolution was conducted by placing an open capsule containing an appropriate weight of beads into a vessel. The results are set forth in Table 3 below: TABLE 3 Hydromorphone HCl 12 mg Controlled Released Capsules Stability Performance Data Time Hydromorphone HCl Average Fill Wt (mg) 1 hr 2 hr 4 hr 8 hr 12 hr 18 hr 24 hr Initial 12.34 259.2 1.5 5.1 15.6 53.5 76.9 93.6 100.0 37°C/80%RH 1 mo. 12.42 262.6 2.1 6.1 12.6 35.1 56.2 75.1 86.1 The above results demonstrate that there was a profound stowing of the dissolution of hydromorphone HCl from the coated beads when the beads were subjected to accelerated storage conditions. EXAMPLE 3 (Comparative) Protecting the Retardant Coating In order to determine if the slowing of the dissolution of the hydromorphone beads of Example 2 was due to a stability problem between the hydromorphone and the retardant, in Example 3 Nu pariel hydromorphone beads were prepared according to Example 1, then overcoated with 5% HPMC, and tested without the retardant layer. Dissolution tests were conducted initially, and after storage at accelerated conditions of 37°C dry and 37°C/80%RH. The results of the dissolution tests for Example 3 are set forth in Table 4 below: TABLE 4 Hydromorphone HCl 8 mg Controlled Release Capsules Stability Data Summary Testing Time Hydromorphone HCI Average Weight (mg) 1 hr 2 hr Initial 8.49 166 100.0 100.0 37°C dry 1 mo. 8.49 167 100.0 100.0 2 mo. 8.49 167 100.0 100.0 37°C/80% RH 1 mo. 8.49 167 100.0 100.0 2 mo. 8.49 170.3 100.0 100.0 The results of Example 3 show that the coated beads which did not include a retardant coating were stable. In order to determine the relative humidity under "dry conditions" in the oven, the relative humidity in a water-filled desiccator in a 60°C oven was determined as follows. First, about 500 grams of purified water is poured into a plastic desiccator and the metal guard inserted. A hygrometer/temperature indicator is placed on top of the guard and the desiccator covered and placed in the 60°C oven for 24 hours. After 24 hours the relative humidity in the desiccator was 85° while the temperature was still 60°C. On placing the hygrometer alone in the 60°C oven for 24 hours, the relative humidity was 9% at 60°C. EXAMPLE 4 (Comparative) Prior Art Curing (According to Literature Recommendations) In Example 4, hydromorphone beads prepared according to Example 3 were coated with the Eudragit® RS to a 5% weight gain. After application of the coating, the beads were dried (cured) at 45°C in a fluidized bed dryer for 2 hours. This temperature is above the Tg of Eudragit® RS 30D, plasticized with Triethylcitrate at 20% level or solids. Dissolution tests were conducted initially, and after storage at 37°C dry and 37°C/80%RH. The results are set forth in Table 5 below: TABLE 5 Hydromorphone HCl 8 mg Controlled Release Capsules Stability Data Summary Testing Time Hydromorphone HCl Average Weight (mg) 1 hr 2 hr 4 hr 8 hr 12 hr 18 hr 24 hr 2 hours * 8.50 178.5 8.0 21.8 45.7 79.3 94.2 37°C dry 1 mo. 8.50 177 16.8 25.8 44.2 67.8 80.8 2 mo. 8.39 174 24.6 40.8 61.8 83.4 94.0 100.0 37°C/80%RH 1 mo. 8.50 174 48.8 60.1 80.7 94.0 100.0 2 mo. 8.55 178 53.6 76.3 90.7 98.2 100.0 *initial dissolution after curing From the results provided above, it can be seen that the hydromorphone dissolution from the beads undervent significant changes upon storage, and that the short curing step recommended in the literature and utilized in Example 4 did not to help the stability/curing problem. EXAMPLES 5-6 (Comparative) PROTECTING THE RETARDANT COATING In Example 5. Eudragit ® -coated beads prepared according to Example 4 were overcoated with 5% HPMC to protect the retardant coating from the environment. Dissolution tests were conducted initially, after storage at room temperature (RT) for 3 months, and after storage at 37°C dry and 37°C/80%RH. The results are set forth in Table 6 below: TABLE 6 Hydromorphone HCl 8 mg Controlled Release Capsules Stability Data Summary Testing Time Hydromorphone HCl Average Weight (mg) 1 hr 2 hr 4 hr 8 hr 12 hr 18 hr 24 hr Initial 8.29 180.5 6.9 17.2 37.5 65.8 80.2 100.0 RT 3 mo. 8.42 178.3 9.4 17.9 63.1 81.6 91.8 97.2 37°C dry 1 mo. 8.29 182 6.4 12.5 28.6 63.9 85.7 100.0 2 mo. 8.56 175 8.1 15.4 31.3 61.9 78.5 89.4 3 mo. 8.30 177 6.8 14.2 30.3 61.4 77.8 89.8 37°C/80%RH 1 mo. 8.29 186.7 7.9 15.7 34.8 68.4 88.0 100.0 2 mo. 8.41 182 9.7 17.6 35.2 66.0 83.2 94.7 3 mo. 8.78 181.7 6.4 12.2 28.2 59.7 77.3 88.4 In Example 6, Eudragit ® -coated beads prepared according to Example 4 which were not cured were overcoated with 5% HPMC to protect the retardant coating from the environment. Dissolution tests were conducted initially, and after storage at 37°C dry and 37°C/80%RH. The results are set forth in Table 7 below: TABLE 7 Hydromorphone HCl 8 mg Controlled Release Capsules Stability Data Summary Time Hydromorphone HCl Average Fill Wt (mg) 1 hr 2 hr 4 hr 8 hr 12 hr 18 hr 24 hr Initial 8.28 178.3 10.7 10.5 34.0 68.3 85.1 RT 3 mo. 8.32 177 5.5 10.5 21.5 57.3 77.9 92.5 37°C dry 1 mo. 8.28 178 1.4 2.4 6.2 27.3 61.8 2 mo. 8.39 177 2.0 6.3 12.6 38.5 70.2 84.6 3 mo. 8.20 172 1.1 4.1 8.8 30.3 61.2 84.6 37°C/80%RH 1 mo. 8.28 176.7 2.3 4.0 9.3 32.7 61.4 2 mo. 8.70 179 2.6 6.5 11.1 35.2 66.6 90.1 3 mo. 8.26 177 1.3 4.1 9.3 30.4 62.3 87.7 As can be seen from the results provided in Tables 6 and 7, other than preventing the spheroids (particularly the Eudragit ® coated spheroids) from agglomerating at accelerated conditions, the terminal HPMC overcoat did not stabilize the products of Examples 5 and 6. On the basis of these results, however, it was hypothesized that, despite the fact that the dissolution changed under accelerated conditions, the cured endpoint could be reached at either dry or moist conditions at 37°C. Examples 7-9 (Examples 7, 8 are comparative) Optimizing Curing and Ingredients of Retardant Coating The results obtained from Examples 2-7 indicated that the dissolution of the beads overcoated with a retardant coating seemed to slow down to a point and no further. However, the endpoint dissolutions achieved were too slow. Since the hydromorphone in the formulations had been protected from the environment, it was hypothesized that exposure to accelerated conditions (e.g., 37°C/80%RH) had the effect of further "curing" the retardant layer. Additional tests were therefore conducted to determine processing conditions required during manufacture to cure the product to its endpoint dissolution. In order to obtain a formulation having a more suitable dissolution curve, and, rather than reduce the coating to less than 5% weight gain, the more soluble Eudragit ® RL (methacrylic ester 1:20 quaternary ammonium groups) was included in the retardant coat. In Examples 7-9. the hydromorphone beads prepared pursuant to Example 5. In Example 7, the retardant coating consisted of 100% Eudragit ® RL In Example 8, the retardant coating consisted of 50% Eudragit ® RL and 50% Eudragit ® RS. Finally, In Example 9, the retardant coating consisted of 10% Eudragit ® RL: Eudragit ® 90% RS. Each of Examples 7-9 were coated to total weight gain of 5%. Each of the HPMC-protected coatings of Examples 7-9 were cured to 1, 2, 6, 8, 12 and 21 days at 45° C dry, at which times dissolution studies as set forth in Example 2 were conducted. Only Example 9 showed a desirable release profile, and curing was complete after only one day. Dissolution studies of the products of Examples 7 and 8 showed the same to be immediate release products, the amount/type of retardant used not being sufficient to prevent immediate release of the drug (i.e.. about 100% of the drug being released after one hour), even after the formulations were cured. Example 9 was further tested by storing under accelerated conditions as follows. After curing for 21 days, the samples of Example 9 were placed in a 37°C/80%RH oven, and dissolution tests as set forth in Example 2 were conducted after 7 and 30 days. Representative dissolution profiles for Example 9 (mean results for three samples) are set forth in Table 8 below: TABLE 8 Hydromorphone HCl 8 mg MD CR Eudragit ® 5% Beads Curing Time Wt(mg) Percent Hydromorphone HCl Dissolved 1 hr 2 hr 4 hr 8 hr 12 hr 18 hr 24hr Initial Mean 191 16.6 53.1 69.3 86.7 95.6 99.3 100.0 1 day Mean 190.7 7.1 33.1 66.6 87.3 99.5 97.9 99.0 2 days Mean 190.7 7.4 35.0 67.0 87.4 95.1 98.4 99.2 7 days Mean 190.7 8.0 36.3 67.7 86.6 93.3 96.8 98.4 10 days Mean 191.3 7.2 36.5 68.9 88.5 94.8 98.0 99.5 21 days Mean 191 6.9 36.1 66.9 86.2 92.7 99.8 99.0 30 days Mean 190.3 5.83 31.9 65.2 82.7 90.4 96.3 96.7 Storage Time/Conditions 30°C/80%RH 7 days Mean 190.7 5.9 25.1 62.7 84.6 92.6 97.6 99.5 30 days Mean 190.3 5.8 31.9 65.2 82.7 90.4 96.3 96.9 The results set forth in Table 8 demonstrate that the 1 month dissolution profile showed no slowdown as compared to the initial cured sample, even for the samples tested under accelerated conditions. Thus, after curing for 24 hours at 45° C, the methacrylate controlled release film coating was essentially stabilized. EXAMPLES 10 - 12 Optimizing Retardant Coating Thickness In Examples 10-12, additional experimentation was conducted to determine the optimum weight of methacrylate polymer to use for a desirable release profile and to determine reproducibility and effectiveness of the 48 hour curing step at 45° C dry. Three batches were manufactured at different levels of methacrylate load and cured in a 45° C dry oven. In Example 10, hydromorphone beads were prepared in accordance with those of Example 3, as set forth in Table 9 below: TABLE 9 Hydromorphone HCl MD Beads Ingredients Percent (by wt) Amt/Unit (mg) Hydromorphone HCl 4.75% 4 Nupariels Pa 18/20 87.89% 74 Opadry Lt Pink Y-5-1442 2.38% 2 Opadry Lt Pink Y-5-1442 4.99% 4.2 100% 84.2 The hydromorphone beads were then further processed in accordance with Example 5. In Example 10, the retardant coating was Eudragit ® RS, Eudragit ® RL 90:10 (5% w/w coating). The formula for Example 10 is set forth in Table 10 below: TABLE 10 Hydromorphone HCl MD CR Eudragit ® 5% Beads Ingredients Percent (by wt) Amt/Unit (mg) Hydromorphone beads 87.96% 84.2 mg Eudragit ® RS 30D (90%) 3.97% 3.8 mg Eudragit ® RL 30D (10%) 0.42% 0.4 mg TEC (20% of RS & RL) 0.88% 0.84mg Talc (40% of RS & RL) 1.75% 1.68mg Purified water qs Opadry Lt Pink Y-5-1442 5.01% 4.8 100% 95.72mg Examples 11 and 12 are prepared in similar fashion to Example 10. In Example 11, the retardant coating was Eudragit ® RS, Eudragit ® RL 90:10 (8% w/w coating). In Example 12, the retardant coating was Eudragit ® RS, Eudragit ® RL 90:10 (12% w/w coating). The formulas for Examples 11 and 12 are set forth in Tables 11 and 12, respectively, below: TABLE 11 Hydromorphone HCl MD CR Eudragit ® 8% Spheres Ingredients Percent (by wt) Amt/Unit (mg) Hydromorphone beads 84.2% 84.2 Eudragit ® RS 30D (90%) 6.07% 6.07 Eudragit ® RL 30D (10%) 0.67% 0.67 TEC (20% of RS & RL) 1.35% 1.35 Talc (40% of RS & RL) 2.70% 2.70 Purified water qs Opadry Lt Pink Y-5-1442 5.0% 5.0 99.99% 99.99 TABLE 12 Hydromorphone HCl MD CR Eudragit ® 12% Spheres Ingredients Percent (by wt) Amt/Unit (mg) Hydromorphone beads 79.69% 84.2 Eudragit ® RS 30D (90%) 8.61% 9.1 Eudragit ® RL 30D (10%) 0.95% 1.0 TEC (20% of RS & RL) 1.91% 2.02 Talc (40% of RS & RL) 3.82% 4.04 Purified water qs Opadry Lt Pink Y-5-1442 5.02% 5.3 100% 105.66 Each of Examples 10-12 were cured on paper lined trays in a 45° C oven for two days after the application of the Eudragit ® Controlled Release Coating and the HPMC 5% overcoating. Dissolution studies were then conducted on Examples 10-12. Initial dissolution profiles (after curing) of Example 10 showed it to resemble Example 9 (the products of both Examples were overcoated with a 5% w/w Eudragit ® coating). After curing for 2 days, samples of Example 10 were subjected to further tests at room temperature, and under accelerated conditions of 37°C/80%RH, 37°C dry and 50°C dry. Representative dissolution profiles for Example 10 (mean results for three samples) are set forth in Table 13 below: TABLE 13 Hydromorphone HCl CR 8 mg Eudragit ® 5% Capsules Percent Hydromorphone HCl Dissolved Time Wt(mg) 1 hr 2 hr 4hr 8 hr 12 hr 18 hr 24hr 2 days* Mean 191.3 6.3 36.2 69.3 87.8 97.3 100.0 RT 1 mo. Mean 191.1 6.0 30.8 63.1 83.4 91.8 96.3 97.9 37°C/80%RH 1 mo. Mean 191.6 6.9 28.5 63.2 84.5 91.5 95.6 97.8 2 mo. Mean 194.3 11.4 35.6 70.7 90.5 96.8 100 37°C Dry 1 mo. Mean 192.0 11.4 35.1 68.6 87.9 94.5 98.9 100 50°C Dry 1 mo. Mean 191.4 11.1 41.4 70.6 90.4 96.5 100 Comparison to Example 9 (1 day and 2 day dissolutions) 1 day Mean 190.7 7.1 33.1 66.6 87.3 99.5 97.9 99.0 2 Days Mean 190.7 7.4 35.0 67.0 87.4 95.1 98.4 99.2 *initial dissolution after curing As can be seen from the dissolution results provided for Example 10, although the dissolution profile of the samples were not taken after 1 day of curing, the results obtained after 2 day curing are substantially similar to the results obtained for the 1 and 2 day curings of Example 9. Therefore, it is hypothesized that the product of Example 10 was also stable after one day curing. After curing for 2 days, samples of Example 11 were tested for dissolution, and then samples of Example 11 were exposed to accelerated conditions of 37°C/80%RH for one month. Representative initial dissolution profiles (mean results for three samples) for Example 11 are set forth in Table 14 below: TABLE 14 Hydromorphone HCl CR 8 mg Eudragit® 8% Capsules Percent Hydromorphone HCl Dissolved Time Wt (mg) 1 hr 2 hr 4 hr 8 hr 12 hr 18 hr 24hr 2 days* Mean 201.3 0.8 3.3 40.0 78.4 90.7 97.5 99.9 37°C/80%RH 1 mo. Mean 7.3 8.6 34.1 72.8 85.5 93.2 97.2 *initial dissolution after curing As can be seen from the dissolution results provided above for Example 11, the results obtained after 2 day curing are substantially similar to the results obtained under accelerated storage conditions of 37°C/80%RH, thus indicating the stability of Example 11 after a 2 day curing. Furthermore, the dissolution results obtained with Example 11 showed slower release rates of hydromorphone, as would be expected given the thicker retardant coating. After curing for 2 days, samples of Example 12 were tested for dissolution, and then samples of Example 12 were subjected to further tests after storing for one month at room temperature, and under accelerated conditions of 37°C/80%RH, 37°C dry and 50°C dry. Representative dissolution profiles (mean results for three samples) for Example 12 are set forth in Table 15 below: TABLE 15 Hydromorphone HCl CR 8 mg Eudragit ® 12% Capsules Percent Hydromorphone HCl Dissolved Time Wt(mg) 1hr 2 hr 4 hr 8 hr 12 hr 18 hr 24hr 2 days* Mean 215.3 0.8 3.1 9.3 70.9 90.4 100.8 104.8 RT 1 mo. Mean 210.8 0 1.8 4.6 62.9 84.3 96.1 99.8 37°C/80%RH 1 mo. Mean 213.8 2.2 4.8 7.2 50.8 74.3 87.3 93.3 37°C Dry 1 mo. Mean 210.4 0.8 2.2 6.9 59.7 82.2 96.3 100 50°C Dry 1 mo. Mean 207.3 1.6 1.5 3.3 51.5 76.2 90.9 97.4 *initial dissolution after curing As can be seen from the dissolution results provided above for Example 12, the dissolution results obtained with Example 12 showed slower release rates of hydromorphone as compared to the thinner retardant coatings of Examples 10 and 11, as expected. The overall results obtained after 2 day curing are substantially similar to the results obtained under accelerated storage conditions of 37°C/80%RH, with the exception of the percent drug dissolved at the 8 hour and 12 hour points. These results might indicate that at high loads of retardant coating, it may be necessary to cure the coating for a longer period of time to attain a stabilized formulation. EXAMPLE 13 Morphine Sulfate Coated Beads In Example 13, the curing step of the present invention was applied to a formulation in which morphine sulfate was substituted as the drug. A suspension of morphine sulfate and HPMC (Opadry ® Clear Y5-7095) was applied onto 18/20 mesh nupariel beads in a fluid bed dryer with a Wurster insert at an inlet temperature of 60°C. An Opadry® Lavender YS-1-4729 HPMC Base filmcoating suspension was then applied after drug loading as a protective coat at a 5% weight gain. After the overcoating process was completed, the morphine sulfate beads were then overcoated with a retardant coating mixture of Eudragit ® RS 30D and Eudragit ® RL 30D at a ratio of 90:10, RS to RL, at a 5% weight gain level. The application of this mixture of Eudragit ® RS 30D and Eudragit ® RL 30D along with talc (included as an anti-tacking agent) and triethyl citrate (plasticizer) was done at an inlet temperature of 35°C in a Wurster Insert. Once the retardant overcoating was complete, the morphine sulfate beads were given a final overcoating of Opadry ® lavender YS-1-4729 at a 5% weight gain level. After completion of the final filmcoating process, the morphine sulfate beads were cured on paper lined trays in a 45°C dry oven for 2 days. After curing, the beads were filled into gelatin capsules at a 30 mg morphine sulfate strength. The final formula is provided in Table 16 below: Table 16 Processing Step Ingredient Mg/Capsule Drug Load Morphine Sulfate 30 mg Nupariel PG 18/20 255 mg Opadry ® Clear Y-5-7095 15 mg First Overcoat Opadry ® Lavender YS-1-4729 15.8 mg Retardant Overcoat Eudragit ® RS 30D 14.2 mg Eudragit ® RL 30D 1.6 mg Triethylcitrate 3.2 mg Talc 6.3 mg Final Overcoat Opadry ® Lavender YS-1-4729 18.0 mg Total: 359.1 mg Dissolution stability studies were then conducted on the product of Example 13 after the above-mentioned curing step at storage conditions of room temperature, 37°C/80%RH, 37°C dry, and 50°C dry after one month and after two months. The results are set forth in Table 17 below: TABLE 17 Morphine Sulfate CR 30 mg Eudragit® 5% Capsules Percent Morphine Sulfate Dissolved Time 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 18 hr 24hr 2 days* Mean 0.0 43.5 74.9 -- 91.8 95.3 99.8 100 RT 1 mo. Mean 0.0 36.9 73.8 86.9 92.2 96.5 99.9 100 2 mo. Mean 2.0 37 72 82 88 92 96 99 37°C/80%RH 1 mo. Mean 0.0 28.4 70.3 84.8 92.1 97.7 100 2 mo. Mean 1.9 30.1 68.4 79.9 87.0 93.5 95.6 97.8 37°C Dry 1 mo. Mean 0.0 32.0 72.5 86.0 93.2 97.3 100 2 mo. Mean 0.9 26.4 67.5 78.8 88.6 94.0 98.0 99.5 50°C Dry 1 mo. Mean 0.0 37.7 74.1 89.3 93.7 98.5 100 2 mo. Mean 2.0 33.0 74 85 94 98 100 *initial dissolution after curing The results set forth in Table 17 demonstrate that the curing process stabilized the dissolution profile of the morphine sulfate to an endpoint dissolution rate which substantially remained constant, even for the samples stored under accelerated conditions. The examples provided above are not meant to be exclusive. Many other variations of the present invention would be obvious to those skilled in the art, and are contemplated to be within the scope of the appended claims.

Claims: A method for obtaining a stabilized controlled release formulation comprising beads coated with an aqueous dispersion of a plasticized acrylic polymer for release of a dose of therapeutically active agent in the gastro-intestinal tract, comprising preparing solid beads comprising a therapeutically active agent, overcoating said substrate with a sufficient amount of a plasticized aqueous dispersion comprising ammonio methacrylate copolymers which are copolymerisates of acrylic and methacrylic esters having a low content of quaternary ammonium groups, in an amount sufficient to obtain a predetermined controlled release of said dose of said therapeutically active agent in the gastro-intestinal tract, characterized in that the curing of said coated beads is affected by subjecting said coated beads to a temperature of about 45° C and greater than the glass transition temperature of the plasticized acrylic polymer for at least 24 hours, and continuing the curing until an endpoint is reached at which said substrate provides a stable dissolution profile, said endpoint being attained, at which the release rate of the therapeutically active agent does not substantially change upon ageing under a wide range of temperature and humidity conditions. The method of claim 1 further comprising determining the endpoint for the formulation by exposing the formulation, which is uncured or substantially uncured, to stressed storage conditions by exposing the formulation to elevated temperature and obtaining dissolution profiles for the formulation until the dissolution profile of the formulation is substantially unaffected by further exposure to elevated temperature and humidity and preferably modifying the formulation by altering the relative amount of different acrylic resin lacquers and/or by increasing or decreasing the thickness of the retardant coating to obtain a desired dissolution profile of said therapeutically active agent based on said endpoint. The method of claim 1 or 2 further comprising preparing said beads for oral administration by coating said therapeutically active agent onto the surface of pharmaceutically acceptable beads, and preparing an oral dosage form by placing a sufficient quantity of cured coated beads into a capsule. The method of any one of claims 1 - 3, wherein said acrylic polymer comprises one or more copolymers of acrylic and methacrylic esters having a content of quaternary ammonium groups, and preferably said acrylic polymer is prepared by mixing a first copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters of about 1:20 with a second copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters of about 1:40, with a suitable plasticizing agent. The method of any one of claims 1-4, wherein said coated beads are cured for a time period from 24 to 48 hours, preferably for 48 hours. The method of any one of claims 1-5, wherein said therapeutically active agent is an antihistamine, analgesic, anti-inflammatory agent, gastro-intestinal, anti-emetic, anti-epileptic, vasodilator, anti-tussive agent, expectorant, anti-asthmatic, anti-spasmodic, hormone, diuretic, anti-hypotensive, bronchodilator, anti-inflammatory steroid, antibiotic, antihemorrhoidal, hypnotic, psychotropic, antidiarrheal, mucolytic, sedative, decongestant, laxative, antacid, vitamin and stimulant, said agent being preferably a hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salt of any of the foregoing and mixture of any of the foregoing, or said therapeutically active agent being theophylline.

Inventors: CHASIN MARK, OSHLACK BENJAMIN, PEDI FRANK JR, CHASIN, MARK, OSHLACK, BENJAMIN, PEDI, FRANK, JR., PEDI, FRANK, JR.,
Applicants: EURO CELTIQUE SA, EURO-CELTIQUE S.A.
Application year: 1992
Main classification: A61K9
IPC codes: A61J3, A61K9, A61M37