MXPA04004035A - Methods and dosage forms for improving the bioavailability of therapeutic agents. - Google Patents

Abstract

The present invention provides controlled release dosage forms for oral administration. The dosage form comprises a therapeutic agent that is metabolized in the upper GI tract in combination with a controlled-release agent so as to be hydrodynamically balanced so that, in contact with gastric fluid, the dosage form has a bulk density less than one g/ml and therefore is buoyant in the gastric fluid. Such dosage form is retained in the stomach during the tinme when substantially all of the medicaments are released therefroom. Additionally, such dosage form will release the medicament over an extended period of time so that delivery of the therapeutic agent to the small intestine will occur steadily rather than immediately. Such steady release over time of the therapeutic agent at the metabolisation and absorption site will prevent enyzme saturation and thereby exhibit greater bioavailability of the therapeutic agent.

Description

METHODS AND FORMS PE DOSES TO IMPROVE THE BIODISPONIBILITY OF THERAPEUTIC AGENTS FIELD OF THE INVENTION The present invention relates to a method for improving the bioavailability of therapeutic agents that are metabolized in the upper gastrointestinal tract (Gl) by administering said agents in a floating dose form. The dosage form is preserved in the stomach for an extended period of time and the therapeutic agent is not released immediately after ingestion. The controlled release of the therapeutic agent from the dosage form prevents enzyme saturation and the bioavailability of the therapeutic agent is improved.

BACKGROUND OF THE INVENTION Many therapeutic agents are metabolized in the upper Gl tract in an active form. This active form is subsequently absorbed through the wall of the intestine. The therapeutic agents are metabolized by the enzymes present in the upper Gl tract. If the therapeutic agent is present in large amounts, the saturation of these enzymes can occur with the result that most of the therapeutic agent passes through the Gl tract without being metabolized and therefore limits the potency of the therapeutic agent.

The conventional controlled release dosage forms have a density greater than that of the gastric contents, furthermore these dosage forms go down to the lower part of the stomach once they are ingested. The "novo" design of controlled drug release systems (SLD) is known in the art to achieve a more predictable bioavailability of drugs. However, it is well known that conventional prolonged release and controlled release SLDs do not overcome adversities such as gastric residence time (T G) and gastric emptying time (TVG). Gastric emptying is the process by which the fasting stomach exhibits a cyclic activity called the migration motor complex. interdigestive (CMMI). The purpose of this cycle is to migrate the contents of the stomach through the pyloric sphincter in the duodenum. The cyclical period C I total is approximately 1.5 to 2.0 hours, although the ingestion of the food interrupts the cycle. [Moes, Critical Reviews in Therapeutic Drug Carrier Systems, 10 (2): 143-195 (1993)]. Due to CMMI, gastric residence of stomach contents, including pharmaceutical forms, is short.

An advance to overcome the adversities of the TRG and TVG is the floating system also known as hydrodynamically balanced systems. It is expected that these systems remain forever floating in the gastric contents without affecting the intrinsic proportion of the emptying due to their volume density is lower than that of gastric fluids. [Moes, Critical Reviews in Therapeutic Drug Carrier Systems, 0 (2): 143-195 (1993)]. The floating forms maintain their low density value while the polymer hydrates and forms a gel. The drug is progressively released from the augmented matrix as in the case of conventional hydrophilic matrices. Id.

U.S. Patent No. 4,167,558 to Sheth et al. Describes a sustained release formulation that is retained in the stomach and slowly releases acetylsalicylic acid. The sustained-release formulation described by Sheth uses a hydrocolloid, which in contact with the gastric fluid at body temperature will form a gelatinous mass on the surface of the tablet, further causing it to lengthen somewhat and acquire a volume density (specific gravity) of less than one. Because the volume density of the tablet is less than that gastric fluid, the tablet remains floating in the gastric fluid and therefore avoids being removed from the stomach during gastric emptying. Acetylsalicylic acid is subsequently slowly released from the gelatinous mass via diffusion.

U.S. Patent No. 5,169,638 to Dennis et al. Describes a capsule filled with loose powder that is floating so that it will float in the gastric juices and therefore improves the bioavailability of the drug. Dennis teaches that the controlled release powder formulation Floating will release a pharmacist of a basic or alkaline character in a controlled proportion relatively independent of the pH of the environment so that consistent release in vivo is achieved through the gastrointestinal tract.

U.S. Patent No. 4,814,179 to Bolton et al. discloses a non-compressed tablet containing the therapeutic agent, the gelling agent, an inert oil therapeutically acceptable and safe. D cha t t t t t D D D D D D D D D D D D D D D D D D D D D D D D D uno D g D g D uno D uno D uno D uno D uno D uno D uno D uno D uno D uno D uno D uno D uno D. D uno D. D. D uno D. D. D. D. D. D. D. D. D. D.

The following is a list of drugs explored by various forms of floating doses (See Singh et al, Journal of Controlled Relay, 63, 240 (2000)).

Microspheres: Aspirin; griseofulvin and p-nitroaniline; Buprobeno; terfenadine; tranilasto.

Granules: Diclofenac sodium; Indomethacin; Prednisolone Tablets / Pills: Acetaminophen, acetylsalicylic acid; amoxicillin trihydrate; ampicillin; atenolol; chlorpheniramine maleate; cinnamisin; diltiazem; fluorouration !; monositrate of sosorbide; isosorbide dinitrate; p-aminobenzoic acid; pyretanide; prednisolone; g luconate of q uinidine; 5'-phosphate of riboflavin; sotalol; theophylline; Verapamil HCL.

Capsules: Clordiazepozide; diazepam; furosemide; L-dopa and bensarazlda; misoprostol; HCI of propranolol; ursodeoxycholic acid.

Movies: Cinarizina.

There are no suggestions anywhere in the prior art that the floating dosage form technology can be used to improve the bioavailability of the therapeutic agents that are metabolized in the upper gastrointestinal tract.

SUMMARY OF THE INVENTION The present invention provides an appropriate formulation for the preparation of controlled release dosage forms for oral administration. The formulation comprises a therapeutic agent that is metabolized in the upper GI tract in combination with the controlled release agent so that they balance hydrodynamically, in contact with the gastric fluid, they have a volume density less than one g / ml and per they are therefore floating in the gastric fluid. Said formulation is retained in the stomach during the time when substantially all drugs are released therein.

The novel method and composition described herein is an original solution for the problem of enzyme saturation of therapeutic agents that are metabolized in the urinary GI tract. It has never been suggested before that the flotation tablet release system could be used to avoid saturation of enzymes. On the other hand, all the prior art reports that the flotation release system is a solution for the short gastric residence time and gastric emptying time. See Stockweil et al., Journal of Controlled Relase, 3, 167 (1986) (Most drugs are optimally absorbed in the small intestine, therefore rapid gastric emptying usually leads to an early bioavailability of the drug. contrast, delayed gastric emptying can provide a prolonged action); Singh et al., Journal of Controlled Relay 63,235,237 (2000) (While the system is floating in the gastric contents, the drug is slowly released in a desired proportion of the system.) This results in an increase in the TRG and better control of the fluctuations in drug concentrations in plasma in some cases); Ingani et al. International Journal of Pharmaceutics, 35 157-164 (1987) (This study has shown that the two-layer floating dose form can be used in a timely manner to increase the gastric residence time of a drug to improve its biological availability).

Using this method for the oral administration of therapeutic agents that are metabolized in the G l tract enhances its bioavailability. The release of these therapeutic agents after more time than the normal immediate release, which exceeds and saturates the enzymes, a more uniform concentration of the substrate over time prevents! excess of the substrate passing the absorption site and therefore being eliminated from the body.

The advantages of this invention include but are not limited to: (1) administration of low doses of therapeutic agents; (2) better control over serum levels of the therapeutic agent and (3) decrease in non-absorption of the therapeutic agent.

In accordance with the invention, controlled release dosage forms are provided, comprising at least one therapeutic agent or pro-drug that is metabolized in the upper Gl tract in an active form, at least one controlled release agent and other excipients. , such as, for example, porosity agents. These controlled release dosage forms are prepared as a floating drug device, which will remain floating in gastric fluids in the stomach after oral administration. Said dosage dosage forms will release the drug over an extended period of time so that the release of the therapeutic agent in the small intestine will occur constantly more than the immediate release. Said constant time release of the therapeutic agent at the site of absorption and metabolization will prevent saturation of the enzyme and therefore exhibit greater bioavailability of the active ingredient.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The present invention provides methods of treatment and dosage forms to improve the bioavailability of a therapeutic agent that is metabolized in the gastrointestinal tract in a active form. Many therapeutic agents are converted to more active species by the superior gastrointestinal enzymes. The high release rates of the therapeutic agents result in the overload of these upper gastrointestinal enzymes. The methods of treatment and the dosage forms of the present invention reduce the dissolution rate of the therapeutic agents while maintaining the dosage form in the stomach for an extended period of time so that the upper gastrointestinal enzymes do not overload and the The patient receives relatively constant plasma levels of the therapeutic agent over an extended period of time.

The controlled release of therapeutic agents has been the subject of extensive searches over the last half of the twentieth century. The controlled release of the therapeutic agents is of high importance because said release allows one or two times a day dosing regimens, which facilitate the loading on the patient and therefore lead to an increased patient condescension. There are several types of polymers that have been used as matrices for the controlled release of drugs. Polymeric materials such as polyvinyl chloride, polyethylene, polyamides, ethylcellulose, silicone, polyhydroxyethyl methacrylate, acrylic co-polymers, polyvinyl acetate-polyvinyl chloride co-polymers and other polymers have been described as suitable matrices for the preparation of controlled release dose (see for example, US Patent No. 3,807,860; US Patent No. 2,987,445 and Pharm. Acta Helv. 1980, 55, 174).

Starch is one of the most attractive biopolymers to be used as a controlled release matrix since it can be a mass produced with a high purity at a very economical price. Amylose is a natural substance obtained from starch. It is essentially an unbranched, linear polymer of the glucopyranose units with a-D (1-4) bonds. In starch, amylose is usually accompanied by smilopectin, which is a branched polyglucose polymer with a significant frequency of branch points based on the α- (1-6) glycosidic linkages.

The crosslinked starch is a controlled release matrix in the solid dosage forms. The crosslinked starch is produced by the reaction of the starch with an appropriate crosslinking agent such as, for example, 2,3-dibromopropanol, epichlorohydrin, phosphorus oxychloride and sodium trimetaphosphate or by thermal crosslinking. A key feature of cross-linked starch is its ability to release therapeutic people as a constant proportion., following the zero order kinetics, as described in S.T.P. Pharma, 1986, 2, 38. Crosslinked starch maintains this controlled release of constant proportion, which functions as a controlled augmentation system. These systems consist of vitreous polymers in which a water front penetrates a constant proportion. Behind this front, the polymer is in an elastic state. The zero-order release is obtained when the diffusion coefficient of the therapeutic agent in the elastic polymer is much higher than in the vitreous polymer. The crosslinked starches producing these desired characteristics as described in US Patent Applications Nos. 09 / 028,385; 09 / 257,090 and 09 / 606,399, the description of which is incorporated herein by reference.

The methods and treatment and dosage forms of the present invention use a controlled release agent incorporated in a floating gel dosage form. Any dosage form currently known in the art such as, for example, tablets, capsules, double layer tablets, double layer capsules, dry coated tablets, dry coated capsules, enteric coated tablets, enteric coated pills, capsules and Enteric-coated capsules can be used as the dosage forms of the present invention. Said flotation gel dosage forms are maintained in the patient's stomach for extended periods of time because they have a relative density less than 1 g / ml and therefore remain floating in the gastric fluids of the patient. The dosage forms of flotation gel may be uniformly constructed or double-layered.

In the chaos of uniform construction, the therapeutic agent, the controlled release matrix, the optional flotation agent and any other additive are mixed homogeneously and subsequently they are formed in the desired dosage form. The flotation agent is optional due to many controlled release agents having a relative density such that a dosage form manufactured therefrom has a sufficiently good elasticity to remain floating. In the case of the construction of two layers, the therapeutic agent and the controlled release matrix are mixed homogeneously and formed in a dosage form. This dosage form is subsequently combined with a dosage form comprising an optional flotation agent and any other additive to produce a two-layer construction dose form, wherein one layer provides flotation and the other layer provides controlled release of the therapeutic agent. Preferably, the dosage form comprises a uniformly sized dosage form, as this construction allows a more efficient manufacture of the dosage form.

Various optional flotation agents can be used to maintain the relative density at a value or less than 1 g / ml. Said flotation agents are celluloses, gums, polysaccharides which include starch and starch derivatives and gelatin. The preferred flotation agents are hydrocolloids. The most preferred flotation agents are the various hydroxypropylmethylcelluloses. Various materials can be added to the flotation agent to improve its cohesion such as, for example, magnesium stearate or various fatty substances. Optionally, sodium bicarbonate, calcium carbonate, lysine carbamate or any other agent that produces carbon dioxide gas (C02) when contacted with gastric acid or an optimum pharmaceutically acceptable acid, such as, for example, citric acid or tartaric acid in the matrix it can be used to increase the flotation.

Additionally, any well-known diluent such as, for example, lactose, sorbitol, mannitol, glucose, microcrystalline cellulose, gelatin, starch, bicalcium phosphate and polyethylene glycol can be added to the dosage form. The preferred diluents are porous agents, such as, for example, lactose.

In addition, the methods of treatment and dosage forms of the present invention use a controlled release matrix in combination with an optional flotation agent to improve the ab ility of a highly soluble therapeutic population by increasing the dosage form = time of administration. gastric residence and provide a controlled release of the therapeutic agent from the dose. The combination of increased gastric residence time and controlled release maintains relatively constant plasma levels by avoiding overload of the upper gastrointestinal enzymes.

The dosage forms of the present invention can be prepared by any method known to one skilled in the art. The dosage form may be tablets, coated tablets, capsules or any other form known to one skilled in the art. Preferably, the dosage form is a capsule of gelatin or of hydroxypropylmethylcellulose (HPMC), wherein the therapeutic agent, the controlled release agent, the optional flotation agent and any additional additives or diluents are mixed homogeneously through the capsule .

EXAMPLE 1 A solid-release, controlled-release, floating gel dosage form was prepared by homogeneously mixing 12 mg of ramiprll, 34.4 mg of CONTRAMID®, 34.4 mg of HPMC K34M, 43.6 mg of lactose and 0.6 mg of silicon dioxide. The homogeneously mixed mixture was placed inside an HPMC capsule.

EXAMPLE 2 A solid-release, controlled-release, floating gel form was prepared by homogeneously mixing 12 mg ramipril, 32.4 mg CONTRAMID®, 32.4 mg HPMC K4M and 48.2 mg mannitol. The mixer is homogenously set up with a CMCMC capsule.

Example 3 A solid-release, controlled-release gel dosage form was prepared by homogeneously mixing 12 mg ramipril, 34.8 mg of CONTRA ID®, 34.8 mg of HPMC K4 and 43.4 mg of polyethylene glycol 8000. The homogenously mixed mixture was placed into One HPMC capsule.

EXAMPLE 4 A solid-release, controlled-release gel dosage form was prepared by homogeneously mixing 12 mg ramipril, 33.2 mg CONTRAMID®, 33.2 mg HPMC K4M and 46.6 mg polyethylene glycol 8000. The homogenously mixed mixture was placed inside. of an HPMC capsule.

Example 5 A solid-release, controlled-release, floating gel dosage form was prepared by homogeneously mixing ramipril 12 mg, CONTRAMID® 30.4 mg, HPMC K4M 30.4 mg, lactose 47.8 mg, sodium bicarbonate 3.1 mg, and 1.3 mg. mg of sodium stearyl fumarate. The homogeneously mixed mixture was placed inside an HPMC capsule.

Example 6 A solid-release, controlled-release, floating gel form was prepared by homogeneously mixing ramipril 12 mg, CONTRAMID® 31.0 mg, HPMC K4M 31.0 mg, lactose 47.8 mg, and sodium bicarbonate 1.9 mg. 3 mg of stearyl sodium fumarate. The homogeneously mixed mixture was placed inside an HPMC capsule.

Example 7 A solid-release, controlled-release gel dosage form was prepared by homogeneously mixing 12 mg ramipril, 31.7 mg CONTRAMID®, 31.7 mg HPMC K4M, 47.7 mg lactose, 0.6 mg sodium bicarbonate and. 3 mg of stearyl sodium fumarate. The homogeneously mixed mixture was placed inside an HPMC capsule.

Example 8 A solid-release, controlled-release, floating gel dosage form was prepared by homogeneously mixing 8 mg ramiprll, 31.6 mg CONTRA ID®, 31.6 mg HP C K4M, 49.5 mg lactose, 3.1 mg sodium bicarbonate and 1.2 mg of stearyl sodium fumarate. The homogeneously mixed mixture was placed inside an HPMC capsule.

Example 9 A solid-release, controlled-release, floating gel dosage form was prepared by homogeneously mixing 8 mg ramipril, 32.9 mg CONTRAMID®, 32.9 mg HPMC K4M, 49.5 mg lactose, 0.6 mg sodium bicarbonate and 1.2 mg. mg of stearyl sodium fumarate. The homogeneously mixed mixture was placed inside an HPMC capsule.

The capsules prepared in Examples 1-9 were subjected to dissolution tests designed to mimic the gastric fluid of a patient. The capsules of Examples 1-9 exhibit controlled release of ramipril. The data for 90% of the ramipril release of each capsule are presented in Table 1.

Table 1 Time measured in hours for 90% of the release of the therapeutic agent from the dosage forms of flotation gel, controlled release, solid.

The capsules prepared in Examples 5-9 were subjected to flotation studies designed to mimic the gastric fluid of a patient. The capsules of Examples 5-9 were placed in a Vankel 7000 test station containing 500 g of dissolution medium consisting of a stabilizer with pH 3.0 of 1.5 ml of 12 M HCl in 20.0 L of deionized water.

The flotation capacity was verified visually in 30-minute intervals. The data for the flotation of each capsule are presented in Table 2.

Table 2 Time measured in hours for the flotation of dosage forms of floating gel, controlled release, solid.

While it is apparent that the methods of invention described in this document are well adapted to meet the objectives set forth above, it will be appreciated that numerous modifications and other modalities may be implemented by those skilled in the art and no attempt is made to appended claims cover all said modifications and modalities that fall within the real spirit and scope of the present invention. A number of references have cited the full description of which are incorporated herein by reference.

Claims (12)

1 A solid controlled controlled release oral dosage form, comprising: a therapeutic agent that is metabolized in the upper gastrointestinal tract and a controlled release agent, wherein the dosage form maintains a bulk density of at least more than about a g / ml, therefore increasing the gastric residence time of the dosage form resulting in an increase in the bioavailability of the therapeutic agent.

2. The solid controlled release oral dosage form according to claim 1 further comprises a flotation people.

3. The solid controlled controlled oral dosage dosage form according to claim 1, further comprising a porosity agent.

4. The solid controlled controlled oral dosage dosage form according to claim 1, wherein the therapeutic agent is an inhibitor of the angiotensin converting enzyme.

5. The solid controlled controlled oral dosage dosage form according to claim 4, wherein the angiotensin-converting enzyme inhibitor is ramipril.

6. The solid controlled controlled release oral dosage form according to claim 2, wherein the flotation agent is selected from the group consisting of hydroxypropylmethylcellulose and polyethylene glycol.

7. The solid controlled controlled oral dosage dosage form according to claim 2, wherein the flotation agent is selected from the group consisting of sodium bicarbonate, sodium carbonate, calcium carbonate and lysine carbamate and further optionally comprises a pharmaceutically acceptable acid selected from the group consisting of citric acid and tartaric acid.

8. The solid controlled controlled release oral dosage form according to claim 1 wherein the controlled release agent is a high crosslinking amylose starch comprising a mixture of approximately 10% to about 60% amylopectin and from about 40%. % to about 90% amylose.

9. The solid controlled controlled oral dosage dosage form according to claim 8, wherein the high crosslinking amylose starch has been covalently crosslinked with a covalent crosslinking agent.

10. The solid controlled controlled oral dosage dosage form according to claim 9, wherein the covalent crosslinking agent is selected from the group consisting of 2,3-dibromopropanol, epichlorohydrin, phosphorous oxychloride and sodium trimetaphosphate.

11. The solid controlled controlled oral dosage dosage form according to claim 3, wherein the porosity agent is selected from the group consisting of lactose, mannitol and sodium bicarbonate.

12. The solid controlled controlled oral dosage dosage form according to claim 11, wherein the porous agent is lactose.