KR20010078703A - New Pharmaceutical Formulation - Google Patents

Abstract

The present invention relates to the preparation of extended release felodipine containing the active compound dissolved or dispersed in a solubilizer and a process for preparing the same.

Description

New Pharmaceutical Formulations

Drugs with very poor water solubility have problems with formulation because of their slow dissolution rate. Their efficacy can be severely limited and their absorption can be varied in large quantities, respectively. Pelodipine is a very low solubility drug. Pelodipine is commonly classified as a calcium antagonist that is widely used for the treatment of cardiovascular disorders such as ischemic heart disease and arterial hypertension. The solubility of felodipine is only 0.5 mg / l in water at 25 ° C.

Several methods of increasing drug absorption have been described in the prior art. One method of increasing absorption of the active compound from the intestine using substituted dihydropyridine, nicardipine, which is rarely soluble, in amorphous form is described in DE-A 3024858. Another method using very small crystals of substantially insoluble dihydropyridine, nifedipine to increase the degree of bioavailability is described in EP-A 47899. These methods and others are also described in "Techniques of solubilization of drugs", Ed S.H. Yalkowsky in Drugs and the pharmaceutical sciences, Vol. 12.]. Particularly suitable for the present invention is that surfactant solubilizers can be used to increase the bioavailability of very low solubility drugs. The improved absorption can be attributed to three actions: (1) increased wettability, (2) increased permeability of the membrane, and (3) solubilization. The cited literature describes several examples and makes good comments on the state of the art regarding the solubilization of drugs, particularly the bioavailability of very poorly soluble drugs.

Controlled release formulations from DE-A 3400106 may comprise one or more natural, partially synthetic or synthetic polymers, one or more lipophilic and / or hydrophilic solvent (s) or thickeners with one or more pharmaceutically active compound (s). It is known to contain (s). Examples in this document describe the use of solubilizers in amounts well below 1: 1 by weight of the active compound.

In medical treatment in the field of various diseases, for example cardiovascular, gastrointestinal and chemotherapy, it is advantageous for the drug administered in the blood to be at a constant concentration. Therefore, it is necessary to prolong the release of the drug from the pharmaceutical formulation.

It is important that extended release formulations deliver the amount of drug necessary to maintain a proper and uniform effect over the entire treatment dosing interval. This generally means that the drug must be delivered at a constant rate so that the concentration of drug administered in the blood is constant. Therapeutic index is particularly important for drugs with small differences between effective and toxic concentrations. Delayed and constant release of the drug will also be important for locally irritating drugs, or drugs with short elimination half-lives, with the potential risk of causing gastrointestinal disorders when present in large local concentrations. In the latter case, extended release formulations may be administered less frequently than conventional dosage forms and may result in better patient compliance (Hayes RB et al. Clin. Pharm. Ther. (1977), 22, p. 125 -130)].

Drugs in extended release form are generally provided via the oral route. Such formulations preferably provide extended and reproducible release of the drug, cause reproducible absorption, and are also suitable for drugs which are free of toxic or irritating ingredients and have high dosages. Typically, extended release is achieved by controlling the dissolution and / or diffusion of the medicament from the dosage form. Several materials are used for this purpose, for example waxes, aliphatic materials, polymers, natural, synthetic and semisynthetic rubbers. Among rubbers, hydroxypropyl methylcellulose (HPMC) constitutes an important group because of its pH-independence as well as its semisynthetic origin. A review of cellulose ethers in hydrophilic matrices for controlled release oral dosage forms is described in Alderman D. A. Int. J. Pharm. Tech. & Prod. Mfr (1984), 5 (3) 1-9. Chemical treatment of HPMCs and the use of these properties to generate the desired structures are disclosed in US 3 087 790, US 4 226 849, US 4 357 469 and US 4 369 172. SE-A 8008646-5 describes a mixture of HPMC and hydroxypropyl cellulose that is used to control the release rate of pharmaceutical active compounds.

If a hydrophilic matrix is used, the soluble polymer forms a gelatin layer around the tablet after the tablet is exposed to gastrointestinal fluid or saliva. The release of the drug is limited by the rate of water penetration, rate of diffusion through the drug, rate of gel formation (Bamba et al. Int. J. Pharm. (1979), 2, 307). Damage to the gel structure is also an important drug release mechanism from the system. The polymer used should be rapidly hydrated to prevent the tablets from dissolving quickly (Alderman 1984).

The rate of absorption into the gastrointestinal circulation of very poorly soluble drugs is highly related to the rate of dissolution. When the dissolution rate is low, since the degree of bioavailability is generally low, it is difficult to reduce the absorption rate, that is, to increase the sustainability at the same time without lowering the degree of bioavailability.

US 4 803 081 discloses extended release formulations of very low solubility active compounds containing the active compounds dissolved or dispersed in semi-solid or liquid nonionic solubilizers, whereby the weight of the solubilizer is the weight of the active compound. That's it.

The present invention relates to extended release pharmaceutical formulations of felodipine and methods of making such formulations.

It is an object of the present invention to obtain a solid preparation with good bioavailability and prolonged release of the active substance.

It is an object of the present invention to provide a felodipine formulation which extends for at least 24 hours and absorbs the drug at a substantially constant rate while maintaining a high degree of bioavailability. Another object is to provide formulations that are easy to prepare. Yet another object of the present invention is to provide a formulation containing a small amount of solubilizer. Suitable solubilizers according to the invention are defined below. The active compound is preferably dissolved or dispersed in the solubilizer. In solution, the drug is included in the micellar structure formed by the solubilizer. Mixtures of drugs and solubilizers are incorporated into pharmaceutical formulations to provide extended release.

In a first embodiment, the present invention relates to polysorbates, polyoxyethylated glycol monoethers, polyoxyethylated alkyl phenols, poloxamers, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, or another fatty acid with PEG A extended release solid preparation of felodipine comprising felodipine dissolved or dispersed in a solubilizer selected from the group consisting of esters, glycerides, sorbitan esters and sucroglycerides.

In another embodiment, the invention relates to polysorbates, polyoxyethylated glycol monoethers, polyoxyethylated alkyl phenols, poloxamers, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, or another fatty acid with PEG The active compound is added to a solubilizer selected from the group consisting of extended release solid preparations of felodipine, which comprises felodipine dissolved or dispersed in a solubilizer selected from the group consisting of esters, glycerides, sorbitan esters and sucroglycerides. After dissolving or dispersing, the mixture is incorporated in a manner known in a suitable release control system to form a pharmaceutical dosage unit, wherein the process relates to the preparation of extended release solid preparations of felodipine.

Solubilizers suitable for the preparations according to the invention are nonionic surface active agents which are semisolid or liquid at ambient temperature, for example, nonionic esters and / or ethers of polyethylene glycol.

a) Complex mixtures of polysorbates-partial esters of sorbitol and their mono- and di-anhydrides condensed with similar moles of ethylene oxide. Eg- Tween; Crillet; Capmul derivatives; Liposorb and the like. See page 375 (see below and Handbook of Pharmaceutical Excipients, 2 ^nd ed; Eds: A Wade and PJ Woller, Pharmaceutical Press 1994).

b) polyoxyethylated glycol monoethers (polyoxyethylene alkyl esters), ie alkyl chains with ethylene oxide chains. Examples are C16E7 (heptaoxyethylene glycol monohexadecylether), Ketomacrogol 1000 BPC, Brij or Atlas series. See page 367 + 556.

c) polyoxyethylated alkyl phenols such as Tritons.

d) Block copolymers (also known as Pluronics) of poloxamers, ie type PEO-PPO-PEO, wherein PEO = polyethylene oxide and PPO = polypropylene oxide with different chain lengths. See page 352.

e) Polyoxyethylene Castor Oil Derivatives-Ethylene oxide (triglyceride of (hydrogenated) stearic acid) reacted with (hydrogenated) castor oil. Yes, Cremophor. See page 371.

f) another fatty acid ester with polyoxyethylene stearate and PEG. Yes, Solutol and Labrasol. See page 379.

g) special substances. Eg TPGS (tocopheryl polyethylene glycol succinate); Glycofurol (see page 213).

Other solubilizers which do not belong to the group of nonionic esters and / or ethers of polyethylene glycol and which are suitable for the preparations according to the invention are as follows.

h) Glycerides (mono-glycerides), e.g. monooolein (glycerol monooleate), camp water, Captex, Imwitor, Gelucire, Myverol ) Etc. See page 207.

i) sorbitan esters-partial esters of sorbitol and their mono- and di-anhydrides with oleic acid, eg Span and the like. See page 473.

j) sucroglycerides-sucrose esters of fatty acids

k) special substances-cyclodextrin solids; See page 147.

a) -g) of the solubilizing agents in the category

Different types of cremophors: Cremophor EL, RH 40, RH 60

Pluronix F127 or F68 (Poloxamer 407 and 188)

Solutol HS 15

-Labrasol

Ketomacrogol 1000 or Breeze 97

And, in the solubilizers within the category h) -k)

Gelushire 44/14 or Gelushire 50/13

-Iwitor 742

Monoolein (glyceryl monooleate) combined with medium chain monoglycerides, ie miberol 18-99 + camp water

Span 20 or Span 80

This is particularly preferred.

The active compound mixed with the solubilizer is incorporated into different types of known controlled release systems, such as hydrophilic gel systems, beads coated with rate controlling membranes, which may be tablets with diffusion delayed coating or degradation coating or inert porous matrix. Can be. The solubilized drug according to the invention is preferably combined with a hydrophilic gel system, ie a hydrophilic swelling matrix (eg HPMC). This form of controlled release mechanism is a suitable method for controlling the release of micelles of drugs and solubilizers. The technical characteristics are good and the in vivo performance is also good. Among the different hydrophilic materials tested, HPMC, hydroxypropyl methylcellulose is the best gel-forming material. Other examples of suitable compounds that affect the release of the active compound from hydrophilic gel systems include guar rubber, xanthan rubber, carboxypolymethylene, different cellulosic materials such as hydroxyethyl cellulose, sodium carboxymethylcellulose and hydroxypropyl Cellulose, lactose, aluminum silicate and polyethylene oxide.

The preparations according to the invention contain 20 to 80% by weight, preferably 30 to 50% by weight of hydrophilic gel system.

Particular preference is given to using HPMC having a hydroxypropyl content of 4 to 12% by weight, in particular about 8.5% by weight and a viscosity of less than 100 cps, for example 6.15 and / or 50 cps. Viscosity is measured by the standardized method described, for example, in United States Pharmacopeia XXI, 1985, p. 672.

The final formulation is for example in the form of a gel tablet. By careful selection of fillers and binders as well as gel-forming substances, the formulations can be prepared in commercially acceptable forms, such as hard gelatin capsules comprising tablets or gel-forming granules, which are unexpectedly well absorbed by the active compound. As well as prolonging active persistence. The ratio between the active compound and the solubilizer in the preparations according to the invention is in the range from 1: 0.01 to 1:10, preferably in the range from 1: 0.1 to 1: 8, and most preferably in the range from 1: 0.5 to 1: 6. Is changed. Optional solubilizers a) -g) are preferably selected in proportions ranging from 1: 0.01 to 1: 1.

Other types of controlled release formulations can also be used in accordance with the invention, for example capsules comprising tablets with inert porous matrices, granules with diffusion delay coatings and dissolution coatings.

Tablets with an inert porous matrix are obtained by mixing drugs and solubilizers with water-insoluble polymers or waxes, and fillers and binders. Polyvinylacetate, polyvinylchloride, ethylcellulose, paraffin and cellulose acetate phthalate can be used as suitable diffusion retarding polymers. Fillers and binders are solid, powder carriers such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin or other suitable carriers. The mixture is wetted with a solvent, for example water or ethanol, or a solution consisting of polymers such as, for example, water and polyvinylpyrrolidone. Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes can also be added. A tablet is then formed from this mixture.

Capsules comprising granules with extended release properties are obtained by preparing a core material containing a drug and a solubilizer together with a filler. The core surface is then coated with a diffusion delay water insoluble polymer or wax. The granules are then filled into hard gelatin capsules. The core material can be prepared, for example, by mixing the drug and solubilizer with carefully selected fillers such as lactose, sorbitol, starch, cellulose derivatives or other suitable fillers. The mixture is wetted with a solvent, for example water or ethanol, or a solution consisting of polymers such as, for example, water and polyvinylpyrrolidone. In this mass, granules are formed, for example, by extrusion and spheronization. The surface of the core formed is coated with a solution consisting of a solvent, for example methylene chloride and / or isopropyl alcohol, and a water insoluble polymer such as ethylcellulose. The granules are filled into hard gelatin capsules.

The following examples illustrate the invention. In all tests, formulations were prepared with different types of polymers and solubilizers. The polymers used were PEO (polyethylene oxide) having a molecular weight of 4,000,000 g / mol (PEO 4 '), 2,000,000 g / mol (PEO 2') and 900,000 g / mol (PEO 0.9 '), two different viscosities (60SH50 and 10,000) HPMC (hydroxypropyl methyl cellulose) with high molecular weight (HEC HHX), medium (HEC HX) and low (HEC M) HEC (hydroxy ethyl cellulose). Surfactants used were SDS (sodium dodecylsulfate), CTAB (cetyl trimethylammonium bromide), gelucrere ^(R), and sulfobetaine. Fillers and lubricants were AMS (aluminum magnesium silicate) and SSF (sodium stearyl fumarate). Tablets were conventionally prepared by dissolving felodipine in ethanol. The mixture of AMS and surfactant was then granulated with felodipine solution. The granules were dried at 50 ° C. for about 16 hours and then mixed with the polymer and SSF. Tablets (diameter = 9 mm) were then made on a Kilian hydraulic compressor with round punches.

In vitro dissolution (drug release)

Tablets were tested using USP Dissolution Apparatus II in 500 ml of phosphate buffer, pH 6.5, containing 0.4% cetyl trimethylammonium bromide (CTAB). A square basket of specially prepared gauze was used to keep the tablets in a defined position in the dissolution vessel. The stirring speed was 100 rpm and the temperature was 37 ° C. Surfactant CTAB was added to the dissolution medium to obtain a sinking state. Samples were collected for analysis (absorbance of felodipine at 362 nm of 1 cm cell). The released amount of felodipine was determined from the scale curve obtained from the absorbance measurements of the standard pelodipine solution based on the same medium as used in the release test.

<Example 1>

Pelodipine formulation in PEO 4 'with felodipine / surfactant = 1/1 (w / w)

Felodipine 5 5 5 5 mg EtOH 99.9 30 30 30 30 mg PEO 4 ' 160 160 160 160 mg AMS 30 30 30 30 mg SDS 5 mg CTAB 5 mg Gelushire 5 mg Sulfobetaine 5 mg SSF 2 2 2 2 mg

Results:% of felodipine released from different formulations of Example 1

Hours / hrs DS CTAB Gelushire Sulfobetaine One 4 4 4 5 2 13 13 12 11 4 29 28 28 27 6 48 45 45 42 8 66 62 64 61 10.3 84 79 82 77

<Example 2>

Pelodipine formulation in PEO 4 'with felodipine / surfactant = 1 / 0.1 (w / w)

Felodipine 5 5 5 5 mg EtOH 99.9 30 30 30 30 mg PEO 4 ' 160 160 160 160 mg AMS 30 30 30 30 mg SDS 0.5 mg CTAB 0.5 mg Gelushire 0.5 mg Sulfobetaine 0.5 mg SSF 2 2 2 2 mg

Results:% of felodipine released from different formulations of Example 2

Hours / hrs DS CTAB Gelushire Sulfobetaine One 4 4 5 6 2 8 9 9 11 4 23 21 24 26 6 40 40 42 44 8 57 55 56 62 11 80 78 79 86

<Example 3>

Pelodipine formulation in PEO 2 'with felodipine / surfactant = 1/1 (w / w)

Felodipine 5 mg EtOH 99.9 30 mg PEO 2 ' 160 mg AMS 30 mg SDS 5 mg SSF 2 mg

Results:% of felodipine released from different formulations of Example 3. Record results from repeated experiments.

Hours / hrs SDS SDS One 9 9 2 20 24 4 34 36 6 58 61 8 77 79

<Example 4>

Pelodipine formulation in 0.9 'PEO with felodipine / surfactant = 1/1 (w / w)

Felodipine 5 mg EtOH 99.9 30 mg PEO 0.9 ' 160 mg AMS 30 mg SDS 5 mg SSF 2 mg

Results:% of felodipine released from different formulations of Example 4. Record results from repeated experiments. Tablets dissolved completely within 6 hours.

Hours / hrs SDS SDS One 15 15 2 38 35 4 85 87

Example 5

Pelodipine formulation in PEO 4 'with felodipine / surfactant = 1/7 (w / w)

Felodipine 5 mg EtOH 99.9 30 mg PEO 4 ' 160 mg AMS 15 mg SDS 35 mg SSF 2 mg

Results:% of felodipine released from different formulations of Example 5.

Hours / hrs SDS One 8 2 16 4 31 6 53 8 63

<Example 6>

Pelodipine formulation in HPMC 60SH50 / 10 000 with felodipine / surfactant = 1/1 (w / w)

Felodipine 5 5 5 5 mg EtOH 99.9 30 30 30 30 mg HPMC 60SH50 56 56 56 56 mg HPMC 10 000 104 104 104 104 AMS 30 30 30 30 mg SDS 5 mg CTAB 5 mg Gelushire 5 mg Sulfobetaine 5 mg SSF 2 2 2 2 mg

Results:% of felodipine released from different formulations of Example 6

Hours / hrs SDS CTAB Gelushire Sulfobetaine One 5 5 4 5 2 11 10 11 10 4 25 21 24 24 6 41 36 39 39 7.5 53 46 51 51 10.5 77 68 73 77

<Example 7>

Pelodipine formulations in HPMC 60SH50 / 10 000 with felodipine / surfactant = 1 / 0.1 (w / w)

Felodipine 5 5 5 5 mg EtOH 99.9 30 30 30 30 mg HPMC 60SH50 56 56 56 56 mg HPMC 10 000 104 104 104 104 AMS 30 30 30 30 mg SDS 0.5 mg CTAB 0.5 mg Gelushire 0.5 mg Sulfobetaine 0.5 mg SSF 2 2 2 2 mg

Results:% of felodipine released from different formulations of Example 7

Hours / hrs SDS CTAB Gelushire Sulfobetaine One 5 5 4 5 2 12 14 12 14 4 25 28 23 25 6 39 45 38 42 8 55 60 53 56

<Example 8>

Pelodipine Formulation in HEC HHX with Pelodipine / Surfactant = 1/1 (w / w)

Felodipine 5 5 5 5 mg EtOH 99.9 30 30 30 30 mg HEC HHX 160 160 160 160 mg AMS 30 30 30 30 mg SDS 5 mg CTAB 5 mg Gelushire 5 mg Sulfobetaine 5 mg SSF 2 2 2 2 mg

Results:% of felodipine released from different formulations of Example 8

Hours / hrs SDS CTAB Gelushire Sulfobetaine One 3 4 4 4 2 6 7 6 7 4 9 10 9 9 10 27 30 27 26 16.3 46 54 57 56 18 51 61 62 61 20 58 69 68 67 22 67 75 72 74 24.5 76 82 78 79

Example 9

Pelodipine Formulation in HEC HHX with Pelodipine / Surfactant = 1 / 0.1 (w / w)

Felodipine 5 5 5 5 mg EtOH 99.9 30 30 30 30 mg HEC HHX 160 160 160 160 mg AMS 30 30 30 30 mg SDS 0.5 mg CTAB 0.5 mg Gelushire 0.5 mg Sulfobetaine 0.5 mg SSF 2 2 2 2 mg

Results:% of felodipine released from different formulations of Example 9

Hours / hrs SDS CTAB Gelushire Sulfobetaine One 5 6 5 6 4.5 12 10 9 10 6 14 14 14 15 8 21 20 20 22 16 42 43 43 45 18 47 49 49 60 22 61 56 56 65 24 67 62 62 72

<Example 10>

Pelodipine formulation in HEC M with felodipine / surfactant = 1 / 0.1 (w / w)

Felodipine 5 mg EtOH 99.9 30 mg HEC M 160 mg AMS 30 mg SDS 5 mg SSF 2 mg

Results:% of felodipine released from different formulations of Example 10. Record results from repeated experiments.

Hours / hrs SDS SDS One 9 9 2 18 21 4 28 30 6 46 49 8 67 65

<Example 11>

Pelodipine Formulation in HEC HX with Pelodipine / Surfactant = 1/1 (w / w)

Felodipine 5 mg EtOH 99.9 30 mg HEC HX 160 mg AMS 30 mg SDS 5 mg SSF 2 mg

Results:% of felodipine released from different formulations of Example 11. Record results from repeated experiments.

Hours / hrs SDS SDS One 3 3 2 8 10 4 24 25 10 66 76

Claims (24)

Polysorbates, polyoxyethylated glycol monoethers, polyoxyethylated alkyl phenols, poloxamers, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, or other fatty acid esters, glycerides, sorbitan esters and water with PEG An extended release solid preparation of felodipine comprising felodipine dissolved or dispersed in a solubilizer selected from the group consisting of croglycerides. The formulation of claim 1 wherein the solubilizer is polyoxyethylated glycol monoether. The formulation of claim 2 wherein the solubilizer is ketomacrogol 1000 or breeze 97. The formulation of claim 1 wherein the solubilizer is poloxamer. The formulation of claim 4 wherein the solubilizer is Pluronix F 127 or F 68. The formulation of claim 1 wherein the solubilizer is a polyoxyethylene castor oil derivative and the ratio of felodipine weight: solubilizer weight is in the range of 1: 0.01 to 1: 1. The formulation of claim 6 wherein the solubilizer is cremophor. The formulation of claim 1 wherein the solubilizer is polyoxyethylene stearate or another fatty acid ester with PEG. The formulation of claim 8 wherein the solubilizer is Solutol HS 15 or Labrasol. The formulation of claim 1 wherein the solubilizer is glycerides. The formulation of claim 10 wherein the solubilizing agent is monoolein in combination with gelusure 44/14, gelusure 50/13, immunocyto 742, medium chain monoglycerides. The formulation of claim 1 wherein the solubilizer is sorbitan ester. The formulation of claim 12 wherein the solubilizer is Span 20 or Span 80. The method of claim 1, wherein the ratio of felodipine weight: solubilizer weight is from 1: 0.01 to 1:10, preferably from 1: 0.1 to 1: 8, and most preferably from 1: 0.5 to Formulations in the range of 1: 6. The formulation of claim 1, wherein the release is controlled by an inert porous matrix, diffusion delay coating or dissolution coating. The formulation of claim 1, wherein the release is controlled by a hydrophilic gel system. The formulation of claim 16, wherein the hydrophilic gel forming component comprises 20 to 80 percent by weight of the formulation. 18. The formulation of claim 16 or 17, wherein the hydrophilic gel system comprises hydroxypropyl methylcellulose. The formulation according to claim 18, wherein the hydroxypropyl content of hydroxypropyl methylcellulose is 4 to 12% by weight. The formulation according to claim 16, wherein the hydrophilic gel system contains carboxypolymethylene. 20. The formulation according to any one of claims 16 to 19, wherein the hydrophilic gel system contains guar rubber or xanthan rubber. 20. The formulation according to any one of claims 16 to 19, wherein the hydrophilic gel system contains a cellulosic material such as hydroxyethyl cellulose, sodium carboxymethyl cellulose or hydroxypropyl cellulose. The formulation of claim 16, wherein the hydrophilic gel system contains lactose, aluminum silicate or polyethylene oxide. Polysorbates, polyoxyethylated glycol monoethers, polyoxyethylated alkyl phenols, poloxamers, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, or other fatty acid esters, glycerides, sorbitan esters and water with PEG After dissolving or dispersing the active compound in a solubilizer selected from the group consisting of extended release solid preparations of felodipine, the mixture is dissolved or dispersed in a solubilizer selected from the group consisting of croglycerides. A process for the preparation of extended release solid preparations of felodipine, characterized by incorporation in a known manner in a suitable release control system to form a pharmaceutical dosage unit.