MX2008005470A - Lipophilic vehicle-based dual controlled release matrix system as capsule fill - Google Patents

Abstract

A lipophilic vehicle-based dual controlled-release matrix, suitable for encapsulation in hard or soft capsules, has been developed. The matrix is in the form of a suspension, which allows for easier formulation of low dose compounds and/or compounds which are moisture sensitive. The matrix includes two rate controlling barriers for the controlled release of one or more pharmaceutically active agents. The primary rate controlling barrier includes a relatively lipophilic oily vehicle. The primary rate controlling barrier may further comprise or more excipients, dissolved in the lipophilic vehicle, which themselves have rate controlling properties. The secondary rate controlling barrier is a hydrogel-forming polymeric material which is dispersed in the primary rate controlling barrier. As the primary rate controlling barrier breaks down, the pharmaceutically active agent is slowly released and the surrounding aqueous media begins to percolate into the polymer matrix. This results in hydration of the polymer and subsequent formation of a hydrogel, which controls the release of the drug by diffusion through, and/or erosion of, the hydrogel. By dispersing or suspending part of the pharmaceutically active agent in the primary rate controlling vehicle, a dual release profile can be obtained. The combination of release of the drug from the lipophilic oily vehicle and release of the drug from the hydrogel allows for the modulation of drug release for up to 24 hours. This system is particularly useful for moisture sensitive drugs as the oily layer prevents water migration from the shell in to the fill.

Description

CONTROLLED DOUBLE RELEASE MATRIX SYSTEM BASED ON A LIQUID VEHICLE AS A CAPSULE FILLER FIELD OF THE INVENTION The present invention is generally in the field of pharmaceutical compositions, specifically controlled release pharmaceutical compositions. BACKGROUND OF THE INVENTION Controlled release (CR) formulations are useful in situations where drug release over a prolonged period of time is required, such as intermittent, repetitive dosages of a drug from one or more immediate release systems. Controlled-release drug delivery systems are used to improve the therapeutic response by providing blood levels that are more consistent and stable compared to the immediate release dosage forms. Existing CR dosage forms typically are based on matrix tablets or coated tablets or capsules filled with coated drug particles or granules. These systems have several disadvantages, however, including the lack of uniformity and homogeneity of the content, particularly with compounds present in low doses. On the other hand, compounds that are used in low doses, as well as compounds that are sensitive to moisture, can be difficult to handle as a solid, which is the form typically used to prepare tablets or hard gelatin capsules filled with powder. U.S. Patent Application Publication No. 2004/0052731 to Hirsh et al. Discloses dissuasive pharmaceutical compositions of abuse. The compositions contain a drug that has been modified to increase its lipophilicity. The modified drug is dispersed with microparticles composed of a material that is either slowly soluble or not soluble in water. Microparticles containing drug or drug particles can be coated with one or more coating layers, wherein at least one coating is insoluble in water and preferably insoluble in organic solvent, but enzymatically degradable by enzymes in the Gl tract. Controlled release formulations, particularly of drugs that are prone to abuse such as opioid analgesics, may be susceptible to misuse. The currently available sustained release formulations of such drugs, which contain a relatively large amount of drug that they propose to be released from the formulation for a prolonged period of time, are particularly attractive to abusers since the sustained release action can be destroyed at crush or grind the formulation. The resulting material (ie, the crushed formulation) can not control the release of the drug for a longer time. Depending on the drug, abusers can then aspirate the material, ingest the material or dissolve the material in water and subsequently inject it intravenously. The dose of drug contained in the formulation is thus immediately absorbed through the nasal mucosa or Gl (for aspiration or ingestion, respectively) or is administered in a bolus to the systemic circulation (for IV injection). These methods result in the rapid bioavailability of relatively high doses of the drug, giving the abuser a "high level". Since relatively simple methods (crushing, grinding, chewing and / or dissolving in water) can be used to transform such formulations into an abusable form, they provide virtually no restraint to a potential abuser. There is a need for a liquid controlled release composition in which low dose compounds and compounds that are sensitive to moisture can be more easily formulated. There is also a need for a controlled release formulation that can minimize or prevent the misuse of drugs that are prone to abuse by making it more difficult for the drug to be extracted from the dosage form.

Therefore, it is an object of the invention to provide a dual controlled release matrix for the formulation of low dose drugs and / or moisture sensitive drugs, and methods of manufacturing thereof. It is a further object of the invention to provide a dual controlled release liquid matrix that can minimize or prevent misuse of drugs that are prone to abuse. BRIEF DESCRIPTION OF THE INVENTION A double controlled release liquid matrix based on a lipophilic vehicle has been developed, suitable for encapsulation in hard or soft capsules. The matrix is in the form of a suspension, which allows the easier formulation of low dose compounds and / or compounds that are sensitive to moisture. The matrix includes two ratio control barriers for the controlled release of one or more pharmaceutically active agents. The primary ratio control barrier includes a relatively lipophilic oily vehicle. The primary ratio control barrier may further comprise one or more excipients, dissolved in the lipophilic carrier, which themselves have proportional control properties. The secondary proportion control barrier is a polymeric hydrogel material that is dispersed in the primary ratio control barrier. According to the control barrier of Primary proportion is degraded, the pharmaceutically active agent is released slowly and the surrounding aqueous medium begins to seep into the polymer matrix. This results in the hydration of the polymer and the formation of a hydrogel, which controls the release of the drug by diffusion through, and / or erosion of, the hydrogel. By dispersing or suspending part of the pharmaceutically active agent in the primary proportion control vehicle, a double release profile can be obtained. The combination of drug release from the lipophilic oily vehicle and drug release from the hydrogel allows modulation of the drug release for up to 24 hours. This system is particularly useful for moisture-sensitive drugs since the oily layer prevents the migration of water from the cover to the fill. The presence of the hydrogel-forming polymeric material, which forms a hydrogel on contact with an aqueous medium, thus trapping the drug, makes the extraction of the drug from the dosage form more difficult. This feature should be beneficial in preventing or minimizing the misuse of dosage forms that contain drugs that are prone to abuse. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the release profile of Diclofenac sodium (% Diclofenac sodium) against time (hours) of a matrix based on lipophilic vehicle. Figure 2 shows the release profile of diltiazem hydrochloride (% diltiazem hydrochloride) against time (hours) of a matrix based on lipophilic vehicle. Figure 3 shows the release profile of Ibuprofen (% Ibuprofen) against time (hours) of a matrix based on lipophilic vehicle. Figure 4 is a schematic view showing the drug release mechanism of a matrix based on lipophilic vehicle. DETAILED DESCRIPTION OF THE INVENTION Liquid controlled release matrix systems suitable for encapsulation have been developed in a soft gelatin capsule, a soft gelatin non-animal capsule, or a hard shell gelatin capsule filled with liquid. The matrix includes a hydrogel-forming polymeric material dispersed in a lipophilic oily carrier. The use of a liquid matrix minimizes the problems associated with the handling of powders, specifically the uniformity and homogeneity of the content thus also eliminating the need for organic solvents that are frequently required in the manufacture of tablets or capsules discovered hard filled with powder. I. Controlled Release Matrix Definitions As used herein, a "double controlled release matrix" refers to a matrix containing a primary ratio control barrier and a secondary proportion control barrier dispersed in the primary ratio control barrier. The primary ratio control barrier includes a lipophilic oily vehicle. The secondary proportion control barrier includes a polymeric hydrogel-forming material. The drug is released from the primary ratio control barrier as the barrier degrades over time. The degradation of the primary ratio control barrier allows water to contact the secondary proportion control barrier resulting in the formation of a hydrogel. The drug molecules trapped within the hydrogel are released over time by diffusion through and / or erosion of the hydrogel. As used herein, "hydrogel" refers to materials that swell considerably in water and dissolve or erode over time depending on the viscosity and molecular weight of the material. As used herein, "lipophilic oily vehicle", "lipophilic vehicle" or "lipophilic base" refers to one or more compounds that are electrically neutral and non-polar. The lipophilic compounds are soluble or partially soluble in fats, oils or lipids. As used herein, a "biphasic release profile" refers to a drug release profile having two distinct phases or stages. As used herein, "controlled release" refers to a release profile of a drug for which the drug release characteristics of the course time and / or location are selected to perform the therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, or readily dissolving dosage forms. Delayed release, prolonged release and pulsatile release and their combinations are types of controlled release. A. Lipophilic Oily Vehicle The hydrogel-forming polymeric material is dispersed in a lipophilic oily vehicle. Exemplary lipophilic oily carriers include, but are not limited to, vegetable oils, medium chain mono-, di-, and triglycerides, glyceryl stearates (available from Sasol ba or the trade name IMWITOR®), polyoxyethylated oleic glycerides (available from Gattefosse , SA, Saint Priest, France, under the trade name LABRAFIL®), mineral oil, mono- and diglyceride emulsifiers such as glyceryl monooleate, glyceryl monocaprate, glyceryl monocaprylate, propylene glycol monocaprylate, and propylene glycol monolaurate (available from Abitec Corp., Columbus, Ohio, under the tradename CAPMUL®), and dimethyl polysiloxanes such as simethicone. The lipophilic oily carrier is present in an amount of from about 3% to about 80% by weight, more preferably from about 15% to about 75%, by weight of the matrix. The incorporation of the drug in a lipophilic vehicle reduces the extractability of the drug. B. Hydrogel Forming Polymers Exemplary hydrogel-forming polymer materials include cellulose ethers, preferably degrees of hypromellose of different viscosity / molecular weight such as hydroxypropyl methyl cellulose (HPMC K4M to K100M available from Dow Chemical); crosslinked acrylates such as CARBOPOL®; alginates; guar or xanthan gum; carrageenan; carboxymethylcellulose; and mixtures thereof. The hydrogel-forming polymeric material is present in an amount of about 2% to about 80% by weight, preferably 3% to 50% by weight, of the matrix. The incorporation of the drug into the hydrogel-forming polymeric material can protect the drug from exposure in mechanical disruption, such as grinding, chewing or cutting, and thus prevent or minimize misuse. In addition, hydrogel-forming polymeric materials they tend to be hydrophilic and thus resist the extraction of the drug trapped by the organic solvents. C. Proportion Control Excipients The lipophilic carrier can be combined with one or more proportion control excipients including, but not limited to, glyceryl behenate, gelucire, cremophor, hydrogenated vegetable oil, beeswax, cellulosic polymers such as hypromellose , alginates, Carbopol® and combinations thereof. A proportion control excipient is defined as a compound having proportion control properties. The one or more excipients are present in an amount of about 50%, more preferably from about 2% to about 30% by weight of the matrix. The lipophilic vehicle may also include one or more surfactants. Suitable surfactants include, but are not limited to, polysorbates (available from ICI under the tradename TWEEN®), sorbitan monoesters (available from ICI under the trade name SPAN®), caprilocaproyl macrogol-8 (available from Gattefosse S.A., Saint Priest, France under the tradename LABRASOL®), cremophores, glyceryl monooleate / stearate and mixtures thereof. The surfactants are present in an amount of about 1% to about 30% by weight of the matrix, preferably about 3% by weight. about 10% by weight of the matrix. By using the appropriate excipients, a biphasic release profile can be obtained, with a rapid initial release of the drug followed by a slow sustained release of the drug. For example, Figure 1 shows the release profile of diclofenac sodium from a double controlled release matrix based on lipophilic vehicle. The system exhibits a release profile wherein approximately 45% of diclofenac sodium has been released after 10 hours and approximately 65% of diclofenac sodium has been released after approximately 25 hours. D. Therapeutic, Prophylactic and Diagnostic Agents Therapeutic, prophylactic or diagnostic agents can be encapsulated. Exemplary drug agents include, but are not limited to, analeptic agents; analgesic agents; anesthetic agents; antiasthmatic agents; antiarthritic agents; anticancer agents; anticholinergic agents; anticonvulsant agents; antidepressant agents; antidiabetic agents; antidiarrheal agents; antiemetic agents; anthelminthic agents; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; anti-inflammatory agents; anti-migraine agents; antineoplastic agents; drugs antiparkinson; antipruritic agents; anti-psychotic agents; antipyretic agents; antispasmodic agents; antitubercular agents; antiulcer agents; antiviral agents; anxiolytic agents; appetite suppressants (anorexic agents); drugs for attention deficit disorder and attention deficit hyperactivity disorder; cardiovascular agents including calcium channel blockers, antianginal agents, central nervous system agents ("CNS"), beta-blockers and antiarrhythmics; stimulants of the central nervous system; diuretics; genetic materials; hormones; hypnotics; hypoglycemic agents; immunosuppressive agents; muscle relaxants; narcotic antagonists; nicotine; nutritional agents; parasitic parasitic; peptide drugs; psychostimulants; sedatives; sialagogues, spheroids; agents to stop smoking; sympathomimetics; tranquilizers; vasodilators; beta-agonist; tocolytic agents and combinations thereof. The agents can be administered as a neutral acid or base or as a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making the acid addition or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, of non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymelic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic. The pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contain a basic or acidic portion, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate acid or base in water or in an organic solvent, or in a mixture of the two; usually, non-aqueous media similar to ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 20th ed. , Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704, the description of which is incorporated herein by reference. E. Excipients and Additives The formulations may include other standard pharmaceutical excipients, including plasticizers, crystallization inhibitors, wetting agents, bulk fillers, solubilizers, bioavailability enhancers, solvents, pH adjusting agents and combinations thereof. II. Capsule Shell Composition A. Gelatin Capsules Gelatin is the product of partial hydrolysis of collagen. Gelatin is classified as either Type A or Type B gelatin. Type A gelatin is derived from the acid hydrolysis of collagen while Type B gelatin is derived from the alkaline hydrolysis of collagen. Traditionally, bovine bones and hides have been used as raw materials for the manufacture of Type A and Type B gelatin, while hogs have been used extensively for the manufacture of Type A gelatin. In general, gelatins processed with acid form gels more stronger than gelatins processed with lime of the same average molecular weight. The capsules can be formulated as hard or soft gelatin capsules. B. Non-Gelatin Capsules Non-Gelatin-Carrageenan Coating Carrageenan is a natural polysaccharide hydrocolloid, which is derived from marine algae. This includes a linear carbohydrate polymer of repeating galactose units, without a significant degree of substitution or branching. Most, if not all, of the galactose units on a carrageenan molecule possess a sulfate ester group. There are three main types of carrageenan: cappa, iota and lambda; although minor forms called carragenan mu and nu also exist. C. Other Coating Additives Other suitable coating additives include plasticizers, opacifiers, colorants, humectants, preservatives, flavors and pH regulating salts and acids. Plasticizers are chemical agents added to gelatin to make the material softer and more flexible. Suitable plasticizers include glycerin, sorbitol solutions which are mixtures of sorbitol and sorbitan, and other polyhydric alcohols such as propylene glycol and maltitol or combinations thereof.

Opacifiers are used to dull the capsule shell when the encapsulated active agents are sensitive to light. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate and combinations thereof. The dyes can be used for marketing purposes and identification / differentiation of the product. Suitable colorants include natural and synthetic dyes and combinations thereof. The humectants can be used to suppress the water activity of the soft gel. Suitable humectants include glycerin and sorbitol, which are often components of the plasticizer composition. Due to the low water activity of soft gels properly stored, dry the largest irrigation of microorganisms comes from molds and yeasts. For this reason, preservatives can be incorporated into the capsule shell. Suitable preservatives include alkyl esters of p-hydroxy benzoic acid such as methyl, ethyl, propyl, butyl and heptyl esters (collectively known as "parabens") or combinations thereof. The flavors can be used to mask off unpleasant odors and flavors of the filling formulations. Suitable flavors include synthetic and natural flavors. The use of flavorings can be problematic due to the presence of aldehydes that can crosslink the gelatin. As a result, the salts and regulating acids can be used in conjunction with flavorings containing aldehyde in order to inhibit the crosslinking of the gelatin. D. Enteric Coatings or Coating Additives Capsules can be encapsulated in, or enclosed within the cover, enteric coatings. In a preferred embodiment using an enteric polymer, the capsule shell is prepared from a mass including a film-forming polymer, an acid-insoluble polymer, an aqueous solvent and optionally a plasticizer. Suitable film-forming polymers include gelatin. Suitable acid-insoluble polymers include copolymers of acrylic acid / methacrylic acid. The acid insoluble polymer is present in an amount of about 8% to about 20% by weight of the wet gel mass. The weight ratio of the acid insoluble polymer to the film-forming polymer is from about 25% to about 50%. The aqueous solvent is water or an aqueous solution of alkalis such as ammonium or diethylene amine or hydroalcoholic solutions thereof. Suitable plasticizers include glycerin and triethyl citrate. The capsules of enteric capsule and a method for making the capsule shell are described in WO 2004/030658 of Banner Pharmacaps, Inc. III. Methods of Elaboration A. Double Controlled Release Matrices The double controlled release matrix can be prepared using a lipophilic vehicle that is a solid or a liquid at room temperature. If the lipophilic carrier is a solid at room temperature, it can be prepared by melting the lipophilic carrier to form a liquid base. Optionally, one or more proportion control excipients, such as glyceryl behanate, polyglycolized glyceride (gelucire), beeswax, hydrogenated oil vegetable or fat vegetable, are solubilized or dispersed in the lipophilic oily carrier. Additional liquid excipients, such as surfactants, may also be dispersed in the lipophilic carrier. Generally, the active agent is first added to a polymeric hydrogel-forming material to form a secondary proportion control barrier; and then the secondary proportion control barrier is dispersed in the lipophilic vehicle. The secondary proportion control barrier is dispersed in the lipophilic oily vehicle by mixing or furnace the hydrogel-forming polymeric material with the lipophilic base at a temperature above the freezing temperature of the lipophilic base. In some modalities, the active agent is dispersed in the lipophilic carrier separately from the hydrogel-forming polymeric material. The active agent is dispersed in the lipophilic vehicle by mixing or homogenization. The filler material, which includes the lipophilic oily vehicle, the hydrogel-forming polymeric material and the active agent, is then deaerated to remove any trapped air, such as by applying a vacuum or a purge with another gas, prior to encapsulation . B. Encapsulation of the Release Matrix Double Controlled The deaired filler material described above can be encapsulated at room temperature or elevated temperatures (up to 35 ° C for soft gelatin capsules and up to 60 ° C for soft shell capsules not for animal) to facilitate filling flow . Encapsulation in the soft-cover capsules is done using a rotary mold encapsulation machine using standard procedures. The capsules are dried to the desired hardness and / or moisture content to facilitate the handling of the capsules during packaging, shipping and storage. Any agent that requires controlled release can be encapsulated in the lipophilic base vehicle matrix with a filling weight range of 100 mg a 2200 mg in a capsule of the right size to swallow. The capsules will be processed following standard procedures and can be packaged either in bottles or bubble pack. EXAMPLES Example 1. Preparation of a Filling Formulation of Diclofenac A dual controlled release matrix system based on lipophilic vehicle containing the following ingredients was prepared.

Glyceryl behanate was dissolved in medium chain triglycerides ("MCT") at about 70 ° C. Aerosil 200, HPMC K4M and HPMC K15M, in that order, were dispersed in the glyceryl / MCT behanate mixture with continuous mixing, just above the freezing temperature of the glyceryl behanate / MCT mixture. Suitable mixers include a mixer with a propeller blade or a blade with teeth of saw or a homogenizer. The diclofenac sodium was dispersed in the above mixture and mixed until a homogeneous mass was obtained. The dough was deaerated to remove any trapped air when applying a vacuum. The mass was then encapsulated in a soft-cover capsule or a hard-shell capsule filled with liquid. The above procedure was used to prepare the diltiazem and ibuprofen hydrochloride filling formulations. In vitro drug release studies were conducted using a USP II dissolution apparatus (paddles) at 50 rpm. The results are shown in Figure 1. The experiments were conducted in dissolution media at a temperature of 37.0 ± 0.5 ° C, for 24 hours in a 6.8 phosphate buffer. Samples were periodically removed and analyzed for diclofenac sodium content using the ultraviolet ("UV") method. The samples were analyzed at a wavelength of 276 nm. Example 2. Alternative Diclofenac Filler Formulation A dual controlled release matrix system based on a lipophilic vehicle containing the following ingredients was prepared.

In vitro drug release studies were conducted using a USP II dissolution apparatus (paddles) at 50 rpm. The results are shown in Figure 1. The experiments were conducted in dissolution media at a temperature of 37.0 ± 0.5 ° C, for 8 hours in a 6.8 phosphate buffer. The samples were periodically removed and analyzed for the content of sodium hydrochloride using the ultraviolet ("UV") method. The samples were analyzed at a wavelength of 276 nm. Example 3. Alternative Diclofenac Filler Formulation A dual controlled release matrix system based on a lipophilic vehicle containing the following ingredients was prepared.

Example 4. Preparation of a Diltiazem Hydrochloride Filling Formulation A dual controlled release matrix system based on a lipophilic vehicle containing the following ingredients was prepared.

The in vitro drug release studies were conducted using a USP II dissolution apparatus (paddles) at 100 rpm. The results are shown in Figure 2. The experiments were conducted in dissolution media at a temperature of 37.0 ± 0.5 ° C, for 24 hours in a 6.5-phosphate buffer. Samples were periodically removed and analyzed for diltiazem content sodium using the ultraviolet ("UV") method. The samples were analyzed at a wavelength of 236 nm. The release profiles of diltiazem hydrochloride are shown in Figure 2. Example 5. Preparation of a Formulation Ibuprofen A double-controlled release matrix system based on lipophilic vehicle containing the following ingredients was prepared.

The in vitro drug release studies were conducted using a USP II dissolution apparatus (paddles) at 100 rpm. The results are shown in Figure 3. The experiments were conducted in dissolution media at a temperature of 37.0 ± 0.5 ° C, for 8 hours in a 7.2 phosphate buffer. The samples were periodically removed and analyzed for the ibuprofen content using the ultraviolet ("UV") method. The samples were analyzed at a wavelength of 276 nm. The profile of Ibuprofen release is shown in Figure 3. Example 6. Preparation of a Fill Formulation of Acetaminophen A double-controlled release matrix system based on lipophilic vehicle containing the following ingredients was prepared.

It is understood that the disclosed invention is not limited to the particular methodology, protocols and reagents described since these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

Claims (22)

1. CLAIMS 1. A dual controlled release liquid matrix for encapsulation in a capsule, the matrix characterized in that it comprises: (a) a primary ratio control barrier comprising a lipophilic oily vehicle; (b) a secondary proportion control barrier comprising a polymeric hydrogel-forming material dispersed in the primary ratio control barrier; and (c) a therapeutic, prophylactic or diagnostic agent entrapped within the primary and secondary ratio control barriers, wherein the release of the therapeutic, prophylactic or diagnostic agent is biphasic.
2. 2. The matrix according to claim 1, characterized in that the lipophilic oily vehicle is selected from the group consisting of vegetable oils; and mono-, di-, and medium chain triglycerides, mineral oil, glyceryl stearates, polyoxyethylated oleic glycerides, glyceryl monooleate, glyceryl monocaprate, glyceryl monocaprylate, propylene glycol monocaprylate, propylene glycol monolaurate, dimethylpolysiloxanes, and combinations thereof .
3. 3. The matrix in accordance with the claim 1, characterized in that the lipophilic oily vehicle is present in an amount from about 3 to about 80% by weight of the matrix.
4. The matrix according to claim 3, characterized in that the lipophilic oily carrier is present in an amount of about 15 to about 75% by weight of the matrix.
5. 5. The matrix according to claim 1, characterized in that the primary ratio control barrier further comprises one or more proportion control excipients.
6. The matrix according to claim 5, characterized in that the proportion control excipients are selected from the group consisting of glyceryl behenate, gelucire, cremophor, hydrogenated vegetable oil, beeswax and combinations thereof.
7. The matrix according to claim 5, characterized in that the proportion control excipients are present in an amount of about 1% to about 50% by weight of the matrix.
8. The matrix according to claim 7, characterized in that the proportion control excipients are present in an amount of about 5% to about 30% by weight of the matrix.
9. 9. The matrix in accordance with the claim 1, characterized in that the primary ratio control barrier comprises one or more surfactants.
10. The matrix according to claim 9, characterized in that the one or more surfactants is selected from the group consisting of polysorbates, sorbitan monoesters, ethoxylated castor oil, caprylocaproyl macrogol-8, glyceryl palmitostearate, glyceryl monooleate / stearate and combinations thereof. .
11. The matrix according to claim 9, characterized in that the one or more surfactants are present in an amount of about 1 to 15% by weight of the matrix.
12. 12. The matrix according to claim 1, characterized in that the hydrogel-forming material is selected from the group consisting of cellulose ethers such as hypromellose, crosslinked acrylates, alginos, xanthan gum, guar, carrageenan, high polyvinyl pyrrolidone. molecular weight and mixtures thereof.
13. 13. The matrix in accordance with the claim 1, characterized in that the hydrogel-forming material is present in an amount of about 1 to about 80% by weight of the matrix.
14. The matrix according to claim 13, characterized in that the hydrogel-forming material it is present in an amount of about 1 to about 50% by weight of the matrix.
15. The matrix according to claim 1, characterized in that the therapeutic, prophylactic and diagnostic agent is dispersed or suspended, in part, in the primary ratio control barrier.
16. 16. The matrix according to claim 1, characterized in that the therapeutic agent is selected from the group consisting of analeptic agents; analgesic agents; anesthetic agents; antiasthmatic agents; antiarthritic agents; anti-cancer agents; anticholinergic agents; anticonvulsant agents; antidepressant agents; antidiabetic agents; antidiarrheal agents; antiemetic agents; anthelminthic agents; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; anti-inflammatory agents; antimigraine agents; antineoplastic agents; antiparkinson drugs; antipruritic agents; anti-psychotic agents; antipyretic agents; antispasmodic agents; antitubercular agents; anti-sulcer agents; antiviral agents; anxiolytic agents; appetite suppressants (anorexic agents); drugs for attention deficit disorder and attention deficit hyperactivity disorder; cardiovascular agents that include channel blockers calcium, antianginal agents, central nervous system agents ("CNS"), beta-blocking agents and antiarrhythmic agents; stimulants of the central nervous system; diuretics; genetic materials; hormones; hypnotics; hypoglycemic agents; immunosuppressive agents; muscle relaxants; narcotic antagonists; nicotine; nutritional agents; parasympatholytics; peptide drugs; psychostimulants; sedatives; sialagogues, spheroids; agents to stop smoking; sympathomimetics; tranquilizers; vasodilators; beta-agonist; tocolytic agents and combinations thereof.
17. 17. The matrix in accordance with the claim 1, characterized in that the therapeutic agent is a drug that is prone to abuse.
18. 18. The matrix in accordance with the claim 1, characterized in that the matrix is encapsulated in a capsule.
19. The matrix according to claim 18, characterized in that the capsule is selected from the group consisting of soft gelatin capsules, hard gelatin capsules, and soft non-gelatin capsules.
20. 20. The matrix according to claim 1, characterized in that the therapeutic, prophylactic and diagnostic agent is modulated for up to 24 hours.
21. 21. A capsule, characterized in that it comprises a Matrix as defined by any one of claims 1 to 17 or 19 to 20.
22. 22. A method for manufacturing a dual controlled release matrix based on lipophilic vehicle for encapsulation in a capsule, the method ac acterized because it comprises dispersing a control barrier of secondary proportion comprising a hydrogel-forming polymeric material and one or more therapeutic, prophylactic or diagnostic agents in a primary ratio control barrier comprising a lipophilic oily carrier, to form a matrix as defined by any one of claims 1 to 20. SUMMARY OF THE INVENTION A double controlled release matrix based on lipophilic vehicle, suitable for encapsulation in hard or soft capsules has been developed. The matrix is in the form of a suspension, which allows the easier formulation of low dose compounds and / or compounds that are sensitive to moisture. The matrix includes two ratio control barriers for the controlled release of one or more pharmaceutically active agents. The primary ratio control barrier includes a relatively lipophilic oily vehicle. The primary ratio control barrier may further comprise one or more excipients, dissolved in the lipophilic carrier, which themselves have proportional control properties. The secondary proportion control barrier is a polymeric hydrogel-forming material that is dispersed in the primary ratio control barrier. As the primary ratio control barrier decomposes, the pharmaceutically active agent is released slowly and the surrounding aqueous medium begins to seep into the polymer matrix. This results in the hydration of the polymer and the subsequent formation of a hydrogel, which controls the release of the drug by diffusion through, and / or erosion of, the hydrogel. By dispersing or suspending part of the pharmaceutically active agent in the control vehicle of primary proportion, a double release profile can be obtained. The combination of drug release from the lipophilic oily vehicle and drug release from the hydrogel allows modulation of the drug release for up to 24 hours. This system is particularly useful for moisture-sensitive drugs since the oily layer prevents migration of water from the cover to the fill.