CN1319004A - new medicinal preparations - Google Patents

Abstract

Extended-release felodipine formulations comprising an active compound dissolved or dispersed in a solubilizing agent and methods for their preparation.

Description

new medicinal preparations

field of invention

The present invention relates to pharmaceutically acceptable extended-release formulations of felodipine and methods of preparing such formulations.

The object of the present invention is to obtain solid preparations with good bioavailability and delayed release of the active ingredient.

Background of the invention

Drugs with poor water solubility present formulation problems due to their slow dissolution rates. Their effects are severely limited and large inter-individual differences can occur. Felodipine is a drug with very low solubility. Felodipine is generally classified as a calcium antagonist, which is widely used in the treatment of cardiovascular diseases such as ischemic heart disease and arterial hypertension. Felodipine has a solubility in water of only 0.5 mg/l at 25°C.

Several approaches to increase drug absorption have been described in the previous literature. A method is described in DE-A-3024858, in which the slightly soluble substituted dihydropyridine nicardipine is used in its amorphous form in order to obtain an increased absorption of the active compound from the intestinal tract. Another approach is described in EP-A-47899, where very small crystals of the very insoluble dihydropyridine nifedipine have been used in order to increase bioavailability. These and other methods are also described in "Pharmaceutical Solubilization Techniques", edited by S.H. Yalkowsky, Drugs and the pharmaceutical sciences, vol. 12. Of particular relevance to the present invention is the use of surfactant solubilizers to increase the bioavailability of drugs with very low solubility. It proposes that the improvement in absorption properties can be attributed to three methods: (1) increased wetting, (2) increased membrane permeability and (3) solubilization. The cited publications describe several examples and give a good overview of the state of the art concerning the solubilization of drugs, especially to increase the bioavailability of drugs with very low solubility.

Controlled-release preparations known from DE-A-3400106 comprise, together with one or more pharmaceutically active compounds, one or more natural, partially synthetic or synthetic polymers, one or more lipophilic and/or Or hydrophilic solvents or thickeners. In the examples it describes the use of solubilizers in amounts (by weight) which are much less than 1:1 for the active compounds.

In the medical treatment of various diseases such as the cardiovascular, gastrointestinal and chemotherapeutic fields, it is advantageous to administer the drug at a constant concentration in the blood. Therefore, there is a need for delayed drug release from pharmaceutical formulations.

It is important that delayed release formulations deliver the amount of drug needed to maintain adequate and uniform action throughout the therapeutic dose interval. This generally means that the drug should give a uniform concentration of drug in the blood at a constant rate. This is especially important for drugs with small therapeutic indices, ie only small differences between effective and toxic concentrations. Delayed and constant release of drugs is also important for locally irritating drugs with a potential risk of causing gastrointestinal disturbances or for drugs with a short elimination half-life when presented in large local concentrations. In the latter case, less frequent dosing and thus better patient compliance can be obtained with delayed-release formulations compared to conventional dosage forms (see Hayes R.B. et al. Clin. Pharm. Ther. (1977) , 22, pp. 125-130).

Drugs are generally administered in delayed release form by the oral route. The formulation should preferably give delayed and reproducible release of the drug and facilitate reabsorption without toxic or irritating components and also be suitable for high doses of the drug. Delayed release is routinely achieved by controlling dissolution and/or diffusion of drug from the dosage form. Several materials are used for this purpose, such as waxes, fatty substances, polymers, natural, synthetic and semi-synthetic gums. Among these gums, hydroxypropylmethylcellulose (HPMC) constitutes an important class due to its pH-independent properties and its semi-synthetic origin. A review of cellulose ethers in hydrophilic matrices for oral controlled release dosage forms is given by Alderman D.A.Int.J.Pharm.Tech. & Prod.Mfr (1984), 5(3) 1-9. Chemical treatment of HPMC to produce the desired structure and the use of these qualities is disclosed in US3087790, US4226849, US4357469 and US4369172. SE-A-8008646-5 describes the combination of HPMC and hydroxypropylcellulose for controlling the release rate of pharmaceutically active compounds.

When a hydrophilic matrix is used, the soluble polymer forms a gel-like layer around the tablet after exposure to gastrointestinal fluids or saliva. Drug release is limited by the rate at which water permeates into and drug diffuses through the gel formed (Bamba et al., Int. J. Pharm. (1979), 2, 307). Erosion of the gel structure is also an important mechanism for drug release from the system. The polymers used must hydrate rapidly to protect the tablet from rapid dissolution (Alderman 1984).

The rate of absorption of a drug with very low solubility from the intestinal tract into the circulation is closely related to the rate of dissolution. Since a low dissolution rate generally results in low bioavailability, it is difficult to reduce the rate of absorption, ie increase the duration without reducing the bioavailability.

US4803081 discloses a delayed release formulation of an active compound with very low solubility, which formulation contains the active compound dissolved or dispersed in a semi-solid or liquid nonionic solubilizer and whereby the amount (by weight) of said solubilizer is at least equal to that of the active compound amount (weight).

Description of the invention

It is an object of the present invention to provide formulations of felodipine which show a prolonged and almost constant rate of drug absorption for a period of at least 24 hours while maintaining a high bioavailability. Another object is to provide formulations which are easy to prepare. Yet another object of the present invention is to provide formulations containing low amounts of solubilizers. Suitable solubilizers according to the invention are defined below. The active compound is preferably dissolved or dispersed in the solubilizer. In the solution, the drug is contained in a micellar structure formed by the solubilizing agent. The mixture of drug and solubilizer is incorporated into the pharmaceutical formulation to give extended release.

In a first embodiment, the present invention relates to a delayed release solid formulation of felodipine comprising felodipine dissolved or dispersed in a solubilizer selected from the group consisting of: polysorbate, polyoxyethylene Glycol monoethers, polyoxyethylated alkylphenols, poloxamers, polyoxyethylene castor oil derivatives, polyoxyethylene stearate or another fatty acid ester with PEG, glycerides , sorbitan esters and glyceryl sucrose esters.

In another embodiment, the present invention relates to a method for the preparation of a sustained-release solid formulation of felodipine, whereby the active compound is dissolved or dispersed in a solubilizer selected from a sustained-release solid formulation of felodipine, characterized in that Comprising felodipine dissolved or dispersed in a solubilizer selected from the group consisting of polysorbates, polyoxyethylated glycol monoethers, polyoxyethylated alkylphenols, poloxamers , polyoxyethylene castor oil derivatives, polyoxyethylene stearate or another fatty acid ester with PEG, glycerides, sorbitan esters and glycerol sucrose esters, after which the mixture is incorporated into in a suitable controlled release system and form pharmaceutical dosage units.

Suitable solubilizers for the formulations according to the invention are semi-solid or liquid nonionic surfactants at ambient temperature, for example nonionic esters and/or ethers of polyethylene glycol:

a) Complex mixtures of partial esters of polysorbate-sorbitol and its mono- and di-anhydrides condensed with an approximate molar amount of ethylene oxide. Examples - Tweens, Crillets, Capmul derivatives, Liposorbs etc. See page 375 (here and following publications are Handbook of Pharmaceutical Excipients, 2nd Edition; Editors: A Wade and PJ Woller, Pharmaceutical Press 1994).

b) Polyoxyethylated glycol monoethers (polyoxyethylene alkyl ethers), ie alkyl chains containing ethylene oxide chains. Examples are C16E7 (heptoxyethylene glycol monocetyl ether), Cetomacrogol 1000 BPC, Brij or the Atlas series. See pages 367+556.

c) Polyoxyethylated alkylphenols, such as Tritons.

d) Poloxamers, ie block copolymers of the type PEO-PPO-PEO, where PEO=polyethylene oxide and PPO=polypropylene oxide with different chain lengths (also called eg Pluronics). See page 352.

e) Polyoxyethylene castor oil derivatives - ethylene oxide reacted with (hydrogenated) castor oil (triglyceride of (hydrogenated) stearic acid). Examples are Chremophors. See page 371.

f) Polyoxyethylene stearate and other fatty acid esters with PEG. Examples are Solutol and Labrasol. See page 379.

g) Special substances such as TPGS (tocopheryl polyethylene glycol succinate); glycofurol (see page 213).

Other solubilizers suitable for the formulation of the present invention that do not belong to nonionic esters and/or polyethylene glycol ethers are:

h) Glycerides (monoglycerides), eg Monoolein (monoolein), Caopmul, Captex, Imwitor, Gelucire, Myverol, etc. See page 207.

i) Sorbitan esters - partial esters of sorbitol and its mono- and di-anhydrides with oleic acid, eg Span et al. See page 473.

j) Glycerol sucrose esters - sucrose esters of fatty acids.

k) Special substance - cyclodextrin solid; see page 147.

Particularly preferred solubilizers are listed in categories a) to g):

- Different types of Chremophor: Cllremophor EL, RH40, RH60

- Pluronics F127 or F68 (poloxamers 407 and 188)

-Solutol HS 15

-Labrasol

-Cetomacrogol 1000 or Brij97

And in directories h)-k):

-Gelucire 44/14 or Gelucire 50/13

-Imwitor 742

- Monoolein (monoolein) bound to medium chain monoglycerides, i.e. Myverol 18-99+Capmul

- Span 20 or Span 80.

The active compound mixed with a solubilizer is incorporated into different kinds of known controlled release systems such as hydrocolloid systems, granules coated with a rate controlling membrane (this membrane may be a delayed diffusion coating or a disintegration coating) or containing In tablets of an inert porous matrix. According to the invention, the drug which can be solubilized is preferably mixed with a hydrophilic colloid system, ie a hydrophilic swelling matrix such as HPMC. This form of controlled release mechanism is a suitable approach for controlling the release of drugs and solubilizers from micelles. The technical properties are good and the in vivo performance is also good. Among the different hydrophilic materials tested, HPMC or hydroxypropyl methylcellulose was the best gelling agent. Other examples of suitable compounds affecting the release of the active compound from the hydrophilic colloid system are guar gum, xanthan gum, carboxypolymethylene, different cellulosic materials such as hydroxyethylcellulose, sodium carboxymethylcellulose and Hydroxypropylcellulose, lactose, aluminum silicate and polyethylene oxide.

The formulations according to the invention contain 20-80% by weight, preferably 30-50% by weight, of the hydrophilic colloid system.

It is particularly preferred to use HPMC with a hydroxypropyl content of 4-12% by weight, especially about 8.5% by weight, and a viscosity below 100 cps, such as 6.15 and/or 50 cps. Viscosity is measured by standard methods such as described in US Pharmacopoeia XXI Edition, 1985, p. 672.

The final formulation is, for example, in the form of a gel tablet. By careful selection of fillers and binders and gelling agents, the formulations can be prepared in a commercially acceptable form, such as tablets or hard gelatin capsules comprising gelled granules, which exhibit unexpected activity of the active compound. Good absorption and prolonged action time. In the formulations according to the invention, the ratio between active compound and solubilizer varies from 1:0.01 to 1:10, preferably from 1:0.1 to 1:8, and most preferably from 1:0.5 to 1: 6 range changes. When selecting any of the solubilizers a)-g), the ratio is preferably in the range from 1:0.01 to 1:1.

Other types of controlled release formulations may also be used according to the invention, such as tablets comprising an inert porous matrix, capsules comprising granules with a diffusion delaying coating or a disintegration coating.

Tablets containing an inert porous matrix are obtained by mixing the drug and solubilizers with water-soluble polymers or waxes together with fillers and binders. Polyvinyl acetate, polyvinyl chloride, ethyl cellulose, paraffin and cellulose acetate phthalate can be used as suitable diffusion retarding polymers. Fillers and binders are solid, powdered carriers such as lactose, sucrose, sorbitol, mannitol, starch, pullulan, cellulose derivatives, gelatin or other suitable carriers. The mixture is wetted with a solvent such as water or ethanol or a solution consisting of, for example, water and a polymer such as polyvinylpyrrolidone. Lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes can also be added. The mixture is then formed into tablets.

Capsules comprising granules with delayed release properties can be obtained by preparing a core material containing drug and solubilizers and fillers. The surface of the core is then coated with a delayed diffusion water insoluble polymer or wax. The granules are then filled into hard gelatin capsules. For example, the core material can be prepared by mixing the drug and solubilizing agent together with carefully selected fillers such as lactose, sorbitol, starch, cellulose derivatives or other suitable fillers. The mixture is wetted with a solvent such as water or ethanol or a solution consisting of, for example, water and a polymer such as polyvinylpyrrolidone. The material is formed into granules, for example by extrusion and agglomeration. The surface of the formed core is coated with a solution of a solvent such as dichloromethane and/or isopropanol and a water-insoluble polymer such as ethylcellulose. The granules are filled into hard gelatin capsules.

Operation example

The following examples illustrate the invention. In all experiments, the formulations were prepared with different types of polymers and solubilizers. The polymers used were: PEO (polyethylene oxide) with molecular weights of 4,000,000 g/mol (PEO 4'), 2,000,000 g/mol (PEO 2') and 900,000 g/mol (PEO 0.9'), with two HPMC (Hydroxypropylmethylcellulose) with different viscosities (60SH50 and 10,000) and HEC (Hydroxyethylcellulose) with high (HEC HHX), medium (HEC HX) and low (HECM) molecular weight. The surfactants used were: SDS (sodium dodecyl sulfate), CTAB (cetyltrimethylammonium bromide), ^Gelucire® and sulfobetaine. Fillers and lubricants are AMS (magnesium aluminum silicate) and SSF (sodium stearyl fumarate). Tablets are generally prepared by dissolving felodipine in ethanol. The mixture of AMS and surfactant was then granulated with the felodipine solution. The granules were dried at 50°C for about 16 hours and then mixed with polymer and SSF. Tablets (diameter = 9mm) were then prepared using a Kilian hydraulic press fitted with round punches.

In vitro dissolution (drug release)

Tablets were tested in 500 ml of phosphate buffer pH 6.5 containing 0.4% cetyltrimethylammonium bromide (CTAB) using a USP dissolution apparatus II. To hold the tablets in the pilot holes in the dissolution vessel, specially prepared square steel wire baskets are used. The stirring rate was 100 rpm and the temperature was 37°C. Surfactant CTAB was added to the dissolution medium to obtain settling conditions. Samples were withdrawn for analysis (absorbance of felodipine at 362 nm in a 1 cm cell). The amount of felodipine released was determined from a calibration curve based on the measured absorbance of a standard felodipine solution in the same medium used in the release experiments. Embodiment 1. Felodipine formulation in PEO 4' of felodipine/surfactant = 1/1 (w/w) Felodipine 5 5 5 5 mg EtOH99.9 30 30 30 30 mg PEO4' 160 160 160 160 mg AMS 30 30 30 30 mg SDS 5 mg CTAB 5 mg Gelucire 5 mg Sulfobetaine 5 mg SSF 2 2 2 2 mg Results: % Release of Felodipine from Different Formulations of Example 1 time/hour SDS CTAB Gelucire Sulfobetaine 1 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 Embodiment 2. Felodipine formulation in PEO4' of felodipine/surfactant = 1/0.1 (w/w) Felodipine 5 5 5 5 mg EtOH99.9 30 30 30 30 mg PEO4' 160 160 160 160 mg AMS 30 30 30 30 mg SDS 0.5 mg CTAB 0.5 mg Gelucire 0.5 mg Sulfobetaine 0.5 mg SSF 2 2 2 2 mg Results: % Release of Felodipine from Different Formulations of Example 2 time/hour SDS CTAB Gelucire Sulfobetaine 1 4 4 5 6 2 8 9 9 11 4 twenty three twenty one twenty four 26 6 40 40 42 44 8 57 55 56 62 11 80 78 79 86 Embodiment 3. Felodipine/surfactant = 1/1 (w/w) Felodipine formulation in PEO2' Felodipine 5 mg EtOH99.9 30 mg PEO 2' 160 mg AMS 30 mg SDS 5 mg SSF 2 mg Results: % release of felodipine from the formulation of example 3. Results from repeated experiments reported time/hour SDS SDS 1 9 9 2 20 twenty four 4 34 36 6 58 61 8 77 79 Embodiment 4. Felodipine formulation in PEO0.9' of 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: % release of felodipine from the formulation of example 4. Results are from reported replicate experiments. Tablets were completely dissolved before 6 hours. time/hour SDS SDS 1 15 15 2 38 35 4 85 87 Embodiment 5. Felodipine formulation in PEO4' of felodipine/surfactant = 1/7 (w/w) Felodipine 5 mg EtOH99.9 30 mg PEO 4' 160 mg AMS 15 mg SDS 35 mg SSF 2 mg Results: % release of felodipine from the formulation of example 5. time/hour SDS 1 8 2 16 4 31 6 53 8 63 Embodiment 6. Felodipine formulation in HPMC 60SH50/10000 of 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 mg AMS 30 30 30 30 mg SDS 5 mg CTAB 5 mg Gelucire 5 mg Sulfobetaine 5 mg SSF 2 2 2 2 mg Results: % release of felodipine from the different formulations of example 6. time/hour SDS CTAB Gelucire Sulfobetaine 1 5 5 4 5 2 11 10 11 10 4 25 twenty one twenty four twenty four 6 41 36 39 39 7.5 53 46 51 51 10.5 77 68 73 77 Embodiment 7. Felodipine formulation in HPMC 60SH50/10000 for 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 10000 104 104 104 104 mg AMS 30 30 30 30 mg SDS 0.5 mg CTAB 0.5 mg Gelucire 0.5 mg Sulfobetaine 0.5 mg SSF 2 2 2 2 mg Results: % release of felodipine from the different formulations of example 7. time/hour SDS CTAB Gelucire Sulfobetaine 1 5 5 4 5 2 12 14 12 14 4 25 28 twenty three 25 6 39 45 38 42 8 55 60 53 56 Embodiment 8. Felodipine/surfactant = 1/1 (w/w) Felodipine formulation in HEC HHX. 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 Gelucire 5 mg Sulfobetaine 5 mg SSF 2 2 2 2 mg Results: % release of felodipine from the different formulations of example 8. time/hour SDS CTAB Gelucire Sulfobetaine 1 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 twenty two 67 75 72 74 24.5 76 82 78 79 Embodiment 9. Felodipine/surfactant = 1/0.1 (w/w) formulation of felodipine in HEC HHX. 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 Gelucire 0.5 mg Sulfobetaine 0.5 mg SSF 2 2 2 2 mg Results: % release of felodipine from the different formulations of example 9. time/hour SDS CTAB Gelucire Sulfobetaine 1 5 6 5 6 4.6 12 10 9 10 6 14 14 14 15 8 twenty one 20 20 twenty two 16 42 43 43 45 18 47 49 49 60 twenty two 61 56 56 65 twenty four 67 62 62 72 Embodiment 10. Felodipine formulation in HEC M with felodipine/surfactant = 1/1 (w/w) Felodipine 5 mg EtOH 99.9 30 mg HEC M 160 mg AMS 30 mg SDS 5 mg SSF 2 mg Results: % release of felodipine from the formulation of Example 10. Reporting results from repeated experiments time/hour SDS SDS 1 9 9 2 18 twenty one 4 28 30 6 46 49 8 67 65 Embodiment 11. Felodipine/Surfactant = 1/1 (w/w) Felodiformulation in HEC HX Felodipine 5 mg EtOH 99.9 30 mg HEC HX 160 mg AMS 30 mg SDS 5 mg SSF 2 mg Results: % release of felodipine from the formulation of example 11. Reporting results from repeated experiments time/hour SDS SDS 1 3 3 2 8 10 4 twenty four 25 10 66 76

Claims (24)

1. Felodipine delayed-release solid preparation, which comprises dissolving or dispersing in polysorbate, polyoxyethylated glycol monoether, polyoxyethylated alkylphenol, poloxamer, poly Felodipine in solubilizers of oxyethylene castor oil derivatives, polyoxyethylene stearate or another fatty acid ester with PEG, glycerol esters, sorbitan esters and glycerol sucrose esters. 2. The formulation of claim 1, wherein said solubilizing agent is polyoxyethylated glycol monoether. 3. The preparation of claim 2, wherein said solubilizer is Cetomacrogol 1000 or Brij97. 4. The formulation of claim 1, wherein said solubilizing agent is a poloxamer. 5. The preparation of claim 4, wherein the solubilizer is Pluronics F127 or F68. 6. The formulation of claim 1, wherein said solubilizing agent is polyoxyethylene castor oil derivative and the weight ratio of felodipine: weight of said solubilizing agent is in the range of 1:0.01 to 1:1. 7. The formulation of claim 6, wherein the solubilizing agent is Chremophor. 8. The formulation of claim 1, wherein the solubilizing agent is polyoxyethylene stearate or another fatty acid ester with PEG. 9. The preparation of claim 8, wherein the solubilizing agent is Solutol HS 15 or Labrasol. 10. The formulation of claim 1, wherein said solubilizing agent is a glyceride. 11. The formulation of claim 10, wherein the solubilizer is Gelucire 44/14, Gelucire 50/13, Imwitor 742, monoolein combined with medium chain monoglycerides. 12. The formulation of claim 1, wherein said solubilizing agent is a sorbitan ester. 13. The formulation of claim 12, wherein the solubilizing agent is Span 20 or Span 80. 14. A formulation according to any one of the preceding claims, wherein the weight ratio of felodipine: weight of said solubilizing agent is in the range of 1:0.01 to 1:10, preferably in the range of 1:0.1 to 1:8, and most preferably Preferably in the range of 1:0.5 to 1:6. 15. A formulation according to any one of the preceding claims, wherein the release is controlled by an inert porous matrix, a diffusion delayed coating or a disintegration coating. 16. A formulation as claimed in any one of the preceding claims, wherein the release is controlled by a hydrophilic colloid system. 17. 16. The formulation of claim 16, wherein said hydrophilic gelling component constitutes 20-80% by weight of the formulation. 18. The formulation of claims 16 and 17, wherein said hydrophilic colloid system comprises hydroxypropylmethylcellulose. 19. 18. The formulation of claim 18, wherein said hydroxypropylmethylcellulose has a hydroxypropyl content of 4-12% by weight. 20. Formulation according to one or more of claims 16-19, wherein said hydrophilic colloid system contains carboxypolymethylene. twenty one. Formulation according to one or more of claims 16-19, wherein said hydrophilic colloid system comprises guar gum or xanthan gum. twenty two. Formulation according to one or more of claims 16-19, wherein said hydrophilic colloid system contains cellulosic materials such as hydroxyethylcellulose, sodium carboxymethylcellulose or hydroxypropylcellulose. twenty three. Formulation according to one or more of claims 16-19, wherein said hydrophilic colloid system contains lactose, aluminum silicate or polyethylene oxide. twenty four. A method for preparing a solid preparation containing felodipine delayed release, characterized in that the active compound is dissolved or dispersed in a solubilizer selected from a solid preparation of felodipine delayed release, characterized in that the method comprises dissolving felodipine In or dispersed in a solubilizer selected from the group consisting of polysorbates, polyoxyethylated glycol monoethers, polyoxyethylated alkylphenols, poloxamers, polyoxyethylene castor oil derivatives, polyoxyethylene stearate or another fatty acid ester with PEG, glycerides, sorbitan esters and glyceryl sucrose esters, the mixture is then incorporated into a suitable controlled release system by known methods And form a pharmaceutical dosage unit.