Patent Application
20070048377
This invention is directed to controlled release pharmaceutical formulations. In particular, the invention is directed to hypromellose-containing powder mixtures which can be used to make controlled release oral solid dosage forms containing a hydrophilic, swellable matrix.
The advantages of controlled release oral solid dosage forms are well known in the pharmaceutical arts. Some of the advantages include once daily dosing, the ability to maintain a desirable blood level of an active pharmaceutical ingredient (hereinafter “API”) over an extended period, such as twenty four hours, minimizing the peak to trough variations in plasma concentrations, etc. Studies also show that patient compliance is increased by reducing the number of daily dosages. While many controlled and sustained release formulations are already known, there continues to be a need to provide improvements and alternatives.
Some efforts in the field of controlled release include those which have incorporated the use of hydrophilic swellable matrices. Drug release from the matrix is accomplished by swelling, dissolution, diffusion and/or erosion. The major component of these systems is a hydrophilic polymer. In general, diffusivity is high in polymers containing flexible chains and low in crystalline polymers. With changes in morphological characteristics, the mobility of the polymer segments will change and diffusivity can be controlled. Often, the addition of other components, such as a drug, another polymer, soluble or insoluble fillers, or solvent, can alter one or more properties of the final product such as the intermolecular forces, free volume, glass transition temperature. Each variable can have an effect on the release rate of the drug from the matrix.
For example, U.S. Pat. No. 6,090,411 describes monolithic tablets containing a swellable hydrodynamically balanced monolithic matrix tablet. The swellable hydrophilic matrix tablet is said to deliver drugs in a controlled manner over a long period of time and be easy to manufacture. The drug is disposed in the HPMC or polyethylene oxide-based matrix, in the presence of a salt.
In another example of such matrix-based tablets, U.S. Pat. No. 6,875,793 discloses controlled release tablets containing a sulfonylurea. The rate controlling feature is based on a matrix containing a polysaccharide blend of materials such as locust bean gum or xanthan gum. The API is dissolved in a suitable solvent before being blended with rate controlling matrix.
In spite of the foregoing, there is also a need in the industry to provide further improvements in the field of controlled release solid dosage forms. For example, it has determined that it would be beneficial to provide the artisan with a pre-mix or partially pre-mixed oral solid dosage formulation which the artisan can quickly adopt for use in the production of new compressed tablets. The present invention addresses this need.
In one aspect of the invention, there is provided a controlled release formulation for use in oral dosage forms. The controlled release formulation includes a mixture of hypromellose and an anionic polymer such as polyvinyl acetate phthalate (hereinafter PVAP). The PVAP is present in the mixture in an amount which is effective to provide controlled release of a pharmaceutically active ingredient when the mixture is compressed into a swellable, hydrophilic matrix. In further aspects, an auxiliary anionic polymer is included in combination with the PVAP and hypromellose. The controlled release of the active pharmaceutical ingredient (API) afforded by the inventive mixture is observed in dissolution media simulated to represent the pH of physiological fluids present over the entire gastrointestinal tract.
The inventive mixture is preferably in powder form and can preferably include an API and/or nutritional supplement. For purposes of the present invention, API shall be understood to include not only pharmaceutical ingredients but also nutritional supplements and/or any other agent or biologically active ingredient suitable for delivery by oral solid dosage forms.
In other aspects of the invention, there are provided oral solid dosage forms containing an API, the inventive powder mixture, preferably in the form of a swellable hydrophilic matrix, and methods of preparing the same.
As a result of the present invention, there are provided new controlled release formulations for the modulation of drug release from HPMC (hypromellose) matrices. It has been surprisingly found the artisan can include PVAP into the matrix to control the release of the API over not only dissolution media intended to simulate the alkaline environments of the GI tract but also dissolution media intended to simulate the neutral and acidic regions of the GI tract as well. In the past, PVAP was believed to be primarily useful for as an enteric coating for compressed tablets. According to the Handbook of Pharmaceutical Excipients Fourth Ed., 2003, PVAP dissolves along the entire length of the duodenum. It was therefore quite surprising that it could be combined with HPMC or hypromellose to modulate the release of API's in neutral and acid environments as well. The combination provides a robust matrix for a full range of highly soluble to practically insoluble active pharmaceutical ingredients.
In a first aspect of the invention, there is provided a controlled release formulation for use in oral dosage forms. The formulation includes a mixture containing hypromellose and polyvinyl acetate phthalate. The amount of PVAP included in the inventive mixture is an amount which is effective to provide controlled release of a pharmaceutically active ingredient in vitro when the mixture is compressed into a swellable, hydrophilic matrix.
Matrix systems are well known in the art. In a typical matrix system, the drug is homogenously dispersed in a polymer in association with conventional excipients. This admixture is typically compressed under pressure to produce a tablet. The API is released from the tablet by diffusion and erosion. Matrix systems are described in detail by (i) Handbook of Pharmaceutical Controlled Release Technology, Ed. D. L. Wise, Marcel Dekker, Inc. New York, N.Y. (2000), and (ii) Treatise on Controlled Drug Delivery, Fundamentals, Optimization, Applications, Ed. A. Kydonieus, Marcel Dekker, Inc. New York, N.Y. (1992), the contents of both of which are hereby incorporated by reference.
When the tablet is exposed to aqueous media, such as in the gastrointestinal tract, the tablet surface wets and the polymer begins to partially hydrate forming an outer gel layer. This outer gel layer becomes fully hydrated and begins to erode into the aqueous fluids. Water continues to permeate toward the core of the tablet permitting another gel layer to form beneath the dissolving outer gel layer. These successive concentric gel layers sustain uniform release of the API by diffusion from the gel layer and exposure through tablet erosion. In the case of the mixtures of the present invention, when included in a compressed tablet matrix, the hypromellose provides a hydrophilic swellable structure capable of functioning as the gel layer while the PVAP portion of the matrix provides means to modulate the thickness of gel formation, hydration rate and water uptake of the tablets. In this way, the drug release is controlled.
For purposes of the present invention, “controlled release” shall be understood to relate to the release of an API from a matrix prepared from the inventive mixture. “Controlled” refers to the ability of the artisan to provide a dosage form with the API being released therefrom in vitro and/or in vivo at a predictable and substantially repeatable rate. As will be appreciated by those of ordinary skill, API release patterns which are “controlled” are not limited to extended or prolonged release profiles. Thus, by “controlled” release of the API, it is to be understood that the API is released predictably after ingestion and/or a period of time which may be extended or otherwise in a manner which is advantageous for the patient receiving the API within acceptable statistical measurements of deviation for the art.
In the case of the present invention, the controlled release of the API can be observed in vitro in dissolution media which simulate the pH of physiological fluids found along the gastrointestinal tract. Formulations of the present invention are associated with API release profiles which can begin within minutes of ingestion, up to and including 24 hours or longer.
The type of hypromellose included in the formulations of the present invention include all such types recognized in the art as being pharmaceutically acceptable. Hypromellose is also known in the art as hydroxypropylmethylcellulose or HPMC and is available from several chemical companies under different trade names. For example, HPMC is available from the Dow Chemical Company under the trade name Methocel®. HPMC's are classified based on their type and level of substitution as well as their solution viscosity at 2% w/v in water at 20° C. A non-limiting list of suitable grades of HPMC includes Methocel K100LV, E-50, K4M, K15M, K100M E4M, E10M, or any grade with a viscosity between 50 and 100,000 centipoise at 20° C.
The amount of hypromellose included in the powder mixtures of the present invention can broadly range from about 8 to about 60% by wt. Preferably, the amount of hypromellose included is from about 15 to about 45% by wt., while in more preferred aspects of the invention, the amount of hypromellose is from about 25 to about 35% by wt. of the powder mixture. In most aspects of the invention, the hypromellose is combined with the PVAP or other anionic polymer, optionally included API, and other carrier materials, and then either direct compressed or wet granulated, fluid bed dried, blended and compressed into a tablet dosage form.
The preferred anionic polymer included in the formulations of the present invention is polyvinyl acetate phthalate which is available, for example, from Colorcon of West Point, Pa. The PVAP included in the present invention may also be co-processed with titanium dioxide, available from Colorcon as PVAP-T. The amount of PVAP and, if desired, auxiliary anionic polymer(s) included in the mixtures of the present invention is described as an amount which is effective to provide controlled release of a pharmaceutically active ingredient when the mixture is compressed into a swellable, hydrophilic matrix. While this amount will vary somewhat according to the needs of the artisan, presence or absence of other ingredients, etc., the amount included will generally be from about 4 to about 60% by wt. of the mixture, preferably from about 8 to about 45% by wt. of the mixture, and more preferably from about 15 to about 35% by wt. of the mixture. As mentioned above, one of the keys to the controlled release aspects of the invention is the use of PVAP to control the release of the API in the GI tract, especially in the acid and neutral regions thereof. In most aspects of the invention, the PVAP (an anionic polymer), will constitute the majority of the anionic polymers included.
In further aspects of the invention, the auxiliary anionic polymer is selected from among pharmaceutically acceptable anionic polymers such as and without limitation, sodium carboxymethylcellulose, sodium alginate, xanthan gum, Carbopol (cross-linked acrylic acid polymers), cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, hydroxyppropylmethyl acetate succinate, and mixtures thereof.
In one aspect of the invention, the hypromellose and PVAP are preferably combined in the form of a mixture, prior to being combined with the API. The mixture can be obtained by dry blending the two ingredients, i.e. hypromellose and PVAP, until an intimate mixture or a substantially homogeneous combination of the ingredients is obtained. It will be understood that those other art-recognized methods of blending can also be employed. The auxiliary anionic polymer can be combined with the PVAP either separately prior to blending with the hypromellose or as part of a tertiary mixture. For ease of discussion, the mixture of the hypromellose and PVAP and, if included, auxiliary anionic polymer, shall be referred to as the “preblend”.
In an alternative aspect, the preblend is made with the API first being combined with the HPMC or the PVAP and optional filler or diluents before being combined with the other mixture components.
It is contemplated that in many preferred embodiments that the powder-based mixtures of the present invention will preferably include a pharmaceutically active ingredient or a nutritional supplement. There are no known limitations on the type of the API which can be included in the powder mixtures and/or hydrophilic matrixes including the same other than that the API must be suitable for inclusion in a hydrophilic matrix and that it must be capable of being included in a solid oral dosage form.
The preblend can be combined with the API in any art-recognized fashion. In some preferred aspects of the invention, the preblend is combined with the API using wet granulation techniques. Other aspects of the invention call for dry blending all components of the oral solid dosage form and using direct compression.
The following non-limiting list of API's is meant to be illustrative rather than restrictive of the API's suitable for inclusion in the powder mixtures of the present invention and/or oral solid dosage forms containing the same:
The artisan will also appreciate that all pharmaceutically active salts or esters of the above and combinations of two or more of the above or salts or esters thereof are also contemplated as are those pharmaceutical agents currently known but not specifically mentioned. In most embodiments of the invention where the API is included, the pharmaceutically active ingredient makes up from about 0.001 to about 60% by weight of the mixture. Preferably, the API makes up from about 5.0 to about 40% by weight of the mixture, while amounts of from about 10 to about 30% by weight of the mixture are more preferred.
In a further aspect, the inventive mixtures and hydrophilic matrixes made therewith include an auxiliary hydrophilic cellulosic polymer. A non-limiting list of suitable auxiliary hydrophobic polymers includes hydroxypropylcellulose, hydroxyethylcellulose, polyvinyl acetate and mixtures thereof. Such auxiliary polymers can be present in amounts ranging from >0 up to about 100% by weight of the hypromellose content.
In a still further aspect of the invention, the hypromellose/PVAP powder mixtures can include one or more pharmaceutically acceptable excipients including but not limited to lubricants, flow aids, diluents, binding agents, disintegrants, binders, solubility enhancers, pH modulating agents, glidants, anti-adherents, etc. and mixtures thereof. Such materials can be present in amounts which range from about 0.001 to about 50% by weight of the total tablet weight. It will be understood that the sum of the individual excipients mentioned below will fall within the range provided.
Suitable lubricants include, for example materials such as stearic acid, metallic stearates (e.g. calcium, magnesium, sodium), polyxamer, polyethylene glycols, e.g. Carbowaxes, hydrogenated vegetable oils such as Sterotex, and mixtures thereof. Suitable flow aids include, for example colloidal silicon dioxide, talc, sodium stearyl fumarate (Pruv), sodium lauryl sulfate, etc. and mixtures thereof. The lubricant can be present in amounts ranging from about 0.1% to about 10%, preferably from about 0.2% to about 8%, and more preferably from about 0.25% to about 5%, of the total weight of the inventive compositions.
Suitable diluents include, for example, microcrystalline cellulose, lactose, dextrose, sucrose, dicalcium phosphate, pregelatanized starch, native starch, mannitol, talc and mixtures thereof. Other suitable inert pharmaceutical diluents include pharmaceutically acceptable saccharides, including monosaccharides, disaccharides or polyhydric alcohols.
If the inventive compositions are to be manufactured without a wet granulation step, and the final mixture is to be tableted, it is preferred that all or part of the inert diluent comprise an art recognized direct compression diluent. Such directed compression diluents are widely used in the pharmaceutical arts, and may be obtained from a variety of commercial sources. Examples include Emcocel. (microcrystalline cellulose, N.F.), Emdex. (dextrates, N.F.), and Tab-Fine (a number of direct-compression sugars including sucrose, fructose and dextrose), or others known to those of ordinary skill. The diluent can be present in amounts ranging from about 0.1% to about 60%, and preferably from about 5% to about 25% by weight of the total tablet weight.
Suitable disintegration aids include, for example, crospovidone, croscarmellose sodium, sodium starch glycolate, hydroxypropylcellulose (low-substituted), starch, calcium carbonate, carboxymethylcellulose calcium, and mixtures thereof. Disintegrants can be added at any suitable step during the preparation of a pharmaceutical composition made according to the methods of the present invention, but are preferably added prior to granulation or during the lubrication step prior to compression. In many aspects of the invention, the disintegrants are present in the range of about 0.5% to about 30%, preferably about 1% to about 10%, and more preferably about 2% to about 6%, of the total weight of the inventive compositions.
Suitable solubility enhancers include, for example, lecithin, poloxamer, polyoxyethylene fatty acid esters, sorbitan esters, and mixtures thereof. Suitable pH modulating agents include for example, citric acid, fumaric acid, tartaric acid, sodium citrate, sodium tartrate, sodium bicarbonate and mixtures thereof.
Suitable binding agents include those well known to those of ordinary skill which preferably impart sufficient cohesion to the powders to permit normal processing such as sizing, lubrication, compression and packaging, but still permit the tablet to disintegrate and the composition to dissolve upon ingestion, for example, povidone, acacia, gelatin, and tragacanth.
Other carrier materials (such as colorants, flavors and sweeteners) can be used in the preparation of the inventive pharmaceutical compositions of the present invention. Tablets made with the inventive compositions can be coated or uncoated. If film coated, materials such as Opadry® (Colorcon) or other art recognized film coating materials are useful.
The formulations according to the invention may be prepared by one or more of the following processes, although other, analogous methods may also be used. In one preferred aspect of the invention, however, the hypromellose and polyvinyl acetate phthalate are wet granulated with a pharmaceutically active ingredient. In other aspects, the primary ingredients, e.g. hypromellose and PVAP are dry blended optionally with the API and auxiliary excipients.
For purposes of illustration, a review of a suitable wet granulation is described below:
In wet granulation techniques, the desired amounts of API, PVAP and diluent are mixed together and thereafter combined with a solution containing a portion of the required hypromellose in the form of a solution under wet granulating conditions. The moistened mass is then dried, granulated and screened before being blended with the remainder of the hypromellose and other optional excipients such as magnesium stearate. The final blend is then ready for tableting.
In a still further embodiment of the invention, there are provided oral solid dosage forms containing the controlled release formulations described herein. Once the inventive powder mixtures are made, such as by dry blending or wet granulation, the mixtures can be compressed into tablets using art recognized techniques. Generally, the artisan can prepare an oral solid dosage form by providing a controlled release formulation described herein and compressing the formulation into an oral solid dosage form using a suitable tablet press.
The following examples serve to provide further appreciation of the invention but are not meant in any way to restrict the effective scope of the invention.
To determine that the influence on the drug release is not due to the chemical interaction between Verapamil HCL and PVAP, following investigation was made.
Compacts Compositions:
Total Tablet Thickness (mm)
A plot of the above data is shown as
Tablet Resistance/Force of Penetration (N) (Mean Force to the First Peak):
A plot of the above data is shown as
c. Results (as summarized in following table):
a. Composition:
In view of the above experiments, we found that increasing levels of PVAP in combination with HPMC have shown a reduction in the drug release of Verapamil hydrochloride. Since a lack of chemical interaction has been shown between PVAP and the drug, the regulation by interaction is ruled out. Texture analysis, tablet mass loss and liquid uptake have shown that as the PVAP level increases, mass loss is reduced and the ingress of water is impeded. This corresponds to reduced conversion of the glassy core into a rubbery gel. This presents itself as a thinner gel around the matrix. This in turn alters the mechanism of release from predominantly diffusion when lactose is present, to predominantly erosion when PVAP is present. As a result, decreased mass loss and decreased drug release are observed for PVAP-containing hypomellose-based formulations. Since all formulations contain a similar level of HPMC for gel formation, the impeding of water ingress is associated with the synergistic interaction of HPMC and PVAP in the presence of water, gastric or intestinal media.
This application claims benefit of priority under 35 U.S.C. 119(e) of U.S. Provisional Application Ser. No. 60/711,724 filed on Aug. 26, 2005, the contents of which are incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60711724 | Aug 2005 | US |
