DE19916384A1 - Microparticles useful in treatment of androgen-dependent disorders include biodegradable, synthetic polymers of e.g. polyesters of hydroxycarboxylic acids - Google Patents

Abstract

Microparticles comprise: (1) cyproterone acetate, chlormadinone acetate or 17 alpha -propyl mesterolone as active agent and (2) wall material comprising biodegradable, synthetic polymers of polyesters of alpha -, beta - or psi -hydroxycarboxylic acids or block copolymers of polyesters of alpha -, beta - or psi -hydroxycarboxylic acids with linear- or star- polyethylene glycols. The microparticle has a diameter of 0.5-20 mu m.

Description

State of the art

The invention relates to new preparations made of microparticles,

• a) the content of cyproterone acetate encapsulated in the microparticles (21- Acetoxy-6-chloro-1,2α-methylene-4,6, -pregnadiene-3,20-dione), chloromadinone acetate (17α- Acetoxy-6-chloro-4,6-pregnadiene-3,20-dione) or 17α-propylmesterolone (17ß-hydroxy-1α- methyl-17α-M-propyl-5α-androsten-3-one),
• b) their wall material made of biodegradable, synthetic polymers of polyesters from α, β or γ hydroxycarboxylic acids or from block copolymers of polyesters of α, β, γ Hydroxycarboxylic acids and linear or star polyethylene glycols,
• c) their active ingredient liberation by choice of the polymer, by the degree of loading, by the Manufacturing technology is controllable,
• d) the diameter suitable for the purpose of "folicular targeting" (approx. 0.5 µm to about 20 µm, but preferably 3 µm to 10 µm) and
• e) in the form of a lyophilisate, a reconstituted lyophilisate or a suspension, a lotion, gel or ointment for topical treatment of androgen-dependent Diseases are used.

It is known that pharmaceutical preparations that have antiandrogenic substances contain, for the treatment of androgen-dependent diseases of women, such as acne, seborrhea, androgen-dependent alopecia and hirsutism used, with all commercially available preparations offered as oral dosage forms become. Because of their systemic, antiandrogenic effectiveness, these preparations are allowed not for the treatment of men suffering from androgen-dependent diseases, such as the Seborrhea or androgen-dependent alopecia can be used. Regarding insists on these applications and the described application limitation urgent need for preparations containing antiandrogenic active ingredients, which a develop good topical effectiveness without the typical systemic side effects demonstrate.

Previously conducted studies on the development of well-tolerated, topical Applicable preparations containing the above-mentioned active ingredients unsatisfactory.  

Interesting new approaches in topical acne therapy (A. Rolland, N. Wagner, A. Chatelus, B. Shroot, H. Schaefer, Pharm. Research, Vol. 10, No. 12, 1993) found that particles smaller than approx. 10 µm accumulate in the hair follicle and or in the stratum corneum.

Description of the invention

The object of the present invention is topically effective antiandrogen-containing Developing preparations that have no antiandrogenic, systemic side effects cause or minimize these side effects.

The microparticles disclosed in this work, loaded with the above-mentioned active substances consist of biodegradable, synthetic polymers of polyesters from α, β or γ Hydroxycarboxylic acids or from block copolymers of polyesters of α, β or γ Hydroxycarboxylic acids and linear or star- polyethylene glycols and have the advantage that they are rapidly degraded in vivo, the degradation products are toxicologically safe are, if desired, large or small amounts of the above-mentioned active ingredients, the active ingredient liberation is easy due to the degree of loading, manufacturing technology and polymer selection controllable, have the correct size for the purpose of "folicular targeting" (i.e. a diameter of about 0.5 microns to about 20 microns, but preferably 3 microns to 10 microns own), can be manufactured easily and quickly, can actually be used in vivo in the Enrich hair foils and use them as a reconstituted lyophilisate or as a suspension, lotion, Cream, ointment or gel can be applied.

The invention therefore relates mainly to the following subjects:

• 1. Microparticles containing active ingredient, characterized in that
  • a) as active ingredient cyproterone acetate (21-acetoxy-6-chloro-1,2α-methylene-4,6, - pregnadiene-3,20-dione), chloromadinone acetate (17α-acetoxy-6-chloro-4,6-pregnadiene- 3,20-dione) or 17α-propylmesterolone (17β-hydroxy-la methyl-17α-M-propyl-5α-androsten-3-one),
  • b) the wall material of the microparticle consists of biodegradable, synthetic polymers of polyesters from α, β or γ hydroxycarboxylic acids or of block copolymers of polyesters of α, β, γ hydroxycarboxylic acids and linear or star polyethylene glycols,
  • c) the microparticles have a diameter of approximately 0.5 μm to approximately 20 μm.
• 2. Use of microparticles according to claim 1 for the production of a Drug.
• 3. Use of microparticles according to claim 1 for producing a Medicinal product for the treatment of androgen-dependent diseases.  
• 4. Use of microparticles according to claim 1 for producing a Lyophilisate, a reconstituted lyophilisate or a suspension, a lotion, a gel or ointment for the treatment of androgen-dependent diseases.

The microparticles according to the invention are produced by processes

• a) which are familiar to the expert ("solvent evaporation, spray drying) and
• b) by optimizing and developing new processes.

The microparticles according to the invention are prepared by dissolving a polymer with one of the above-mentioned active ingredients in an organic solvent. This solution will either

• a) mechanically in an aqueous surfactant solution (e.g. using a stirrer or Ultra-Turrax) dispersed,
• b) spray dried or
• c) pressed through defined pores of a glass membrane and from a circulating, aqueous surfactant solution.

The organic solvent is then applied by applying a vacuum and / or an air / nitrogen stream removed from the O / W emulsion. The generated Microparticles can (if desired) be washed (i.e. centrifuged or cross-flow) filtered) and concentrated and can then, if desired, with a Cryoprotector (i.e. a sugar, sugar alcohol or other substances such as gelatin, Polyvinylpyrrolidone etc.) can be frozen and freeze-dried.

The following polyesters of hydroxycarboxylic acids are preferably used to produce the antiandrogen-loaded polymer microcapsules:

Polyglycolide (PGA)
Copolymers of glycolide
Glycolide / l-lactide copolymers (PGA / PLLA)
Glycolide / trimethylene carbonate copolymeres (PGA / TMC)

Polylactides (PLA)
Stereocopolymers of PLA:
Poly-L-Lactide (PLLA)
Poly-DL-lactide copolymers
L-lactide / DL-lactide copolymers
Copolymers of PLA
Lactide / tetramethylglycolide copolymers
Lactidel Trimethylene carbonate copolymers
Lactide / δ-valerolactone copolymer
Lactide / ε-caprolactone copolymer

Poly-β-hydroxybutyrate (PHBA)
PHBA / β-hydroxyvalerate copolymers (PHBA / HVA)
Poly-β-hydroxypropionate (PHPA)
Poly-p-dioxanones (PDS)
Poly-δ-valerolactones
Poly-ε-caprolactones

The following block copolymers of polyesters of hydroxycarboxylic acids and linear or star polyethylene glycol are preferably used to produce the anti-androgen-loaded polymer microcapsules:

* PLA PEG AB block copolymers
PLA PEG PLA ABA block copolymers
S (3) -PEG-PLA block copolymers
S (4) -PEG-PLA block copolymers

The following are preferably used as organic solution or solvent mixtures:

• - dichloromethane
• - 1, 2 dichloroethane
• - chloroform
• - carbon tetrachloride
• - acetone
• - ethyl acetate
• - methyl acetate
• - triacetin
• - triethyl citrate
• - ethyl lactate
• - methyl lactate
• - propyl acetate
• - isopropyl acetate
• - Buy acetate
• - propyl formate  
• - isopropyl formate
• - butyl formate
• - ethyl formate
• - methyl formate

Preferred (a) substance (s) from the Poloxamer® group, polyethylene glycol alkyl ether, polysorbates (Tweene, Span®), Sucrose ester (Sisterna®, the Netherlands) sucrose ester (Ryoto sugar ester, Tokyo), Gelatin, polyvinylpyrolidone, fatty alcohol polyglycoside, Charps, Charpso, Decyl β-D- Glycopyranoside, decyl β-D-maltopyranoside, dodecyl β-D-maltopyranoside, sodium oleate, Poloxamin® group, polyethylene glycol, polyvinyl alcohol, polyoxyethylated fatty acid ethers (Brij®), Triton X 100 or mixtures thereof.  

The invention is (without being limited to the examples mentioned) by The following examples illustrate:

example 1

50 ml of a 2% polyvinyl alcohol solution (molecular weight 9000-10000, Aldrich) transferred to a steel vessel (height 11.5 cm, inner diameter 8 cm). Subsequently 10 ml of a solution consisting of 5 ml of ethyl acetate, 5 ml of dichloromethane, 0.5 g Resomer® RG 858, 0.4 g cyproterone acetate using a mechanical stirrer (Dispermat-FT, VMA Getzmann GmbH, 5 cm dissolver disc) in the polymer solution 30 dispersed at 10,000 rpm under room temperature. The resulting O / W emulsion is transferred to a 500 ml three-necked flask and stirred using a KPG stirrer. The organic solvent mixture is then below 20 ° C by applying a vacuum (900 mbar), nitrogen or air inlet removed. After 5 h, the suspension with 5 L Washed water or an aqueous solution (i.e. from excess active ingredient and Residual solvent freed) and concentrated to a desired suspension volume. Advantageous is the use of a "cross flow" filtration, for example a Sartocon Mini® (Sartorius AG, Göttingen) System with a polyolefin membrane (cutoff 0.2 µm). The solvent and almost emulsifier-free suspension can be used with a croprotector (e.g. with a sugar, sugar alcohol or polyvinylpyrrolidone derivative) and will frozen and freeze-dried.

Contains the lyophilisate resuspended with water or with an aqueous solution surprisingly microparticles with a cyproterone content of 42% (Cyproterone mass * 100 / Cyproterone mass + polymer mass). 99% of all microparticles are smaller than 5.7 µm.

Example 2

50 ml of a 2% polyvinyl alcohol solution (molecular weight 9000-10000, Aldrich) transferred to a steel vessel (height 11.5 cm, inner diameter 8 cm). Subsequently 10 ml of a solution consisting of 5 ml of ethyl acetate, 5 ml of dichloromethane, 0.5 g Resomer® RG 858, 0.8 g cyproterone acetate using a mechanical stirrer (Dispermat-FT, VMA-Getzmann GmbH, 5 cm dissolver disc) in the polymer solution 30 dispersed at 10,000 rpm under room temperature. The resulting O / W emulsion is transferred to a 500 ml three-necked flask and stirred using a KPG stirrer. The organic solvent mixture is then below 20 ° C by applying a vacuum (900 mbar), nitrogen or air inlet removed. After 5 h, the suspension with 5 L Washed water or an aqueous solution (i.e. from excess active ingredient and Residual solvent freed) and concentrated to a desired suspension volume. Advantageous  is the use of a "cross flow" filtration, for example a Sartocon Mini® (Sartorius AG, Göttingen) System with a polyolefin membrane (cutoff 0.2 µm). The solvent and almost emulsifier-free suspension can be used with a croprotector (e.g. with a sugar, sugar alcohol or polyvinylpyrrolidone derivative) and will frozen and freeze-dried.

Contains the lyophilisate resuspended with water or with an aqueous solution surprisingly microparticles with a cyproterone content of 58% (Cyproterone mass * 100 / Cyproterone mass + polymer mass). 99% of all microparticles are smaller than 10.4 µm.

Example 3

50 ml of a 2% polyvinyl alcohol solution (molecular weight 9000-10000, Aldrich) transferred to a steel vessel (height 11.5 cm, inner diameter 8 cm). Subsequently 10 ml of a solution consisting of 10 ml of ethyl acetate, 0.5 g of Resomer® RG 858, 0.2 g Cyproterone acetate using a mechanical stirrer (Dispermat-FT, VMA-Getzmann GmbH, 5 cm dissolver disc) in the polymer solution for 30 seconds at 10000 rpm Dispersed room temperature. The resulting O / W emulsion is poured into a 500 ml Three-neck flask transferred and stirred using KPG stirrer. The organic The solvent mixture is then below 20 ° C by applying a vacuum (900 mbar), Nitrogen or air intake removed. After 5 h, the suspension with 5 L of water or washed in an aqueous solution (i.e. excess active ingredient and residual solvent freed) and concentrated to a desired suspension volume. The use is advantageous a "cross flow" filtration, for example a Sartocon Mini® (Sartorius AG, Göttingen) System with a polyolefin membrane (cutoff 0.2 µm). The solvent and approximate emulsifier-free suspension can be used with a croprotector (e.g. with a sugar, Sugar alcohol or polyvinylpyrrolidone derivative) are added and is frozen and freeze-dried.

Contains the lyophilisate resuspended with water or with an aqueous solution surprisingly microparticles with a cyproterone content of 29% (Cyproterone mass * 100 / Cyproterone mass + polymer mass). 99% of all microparticles are smaller than 8.2 µm.  

Example 4

The procedure is as in Example 1, with 0.7 g of Resomer® instead of 0.5 g of Resomer® RG 858 502 is used.

Example 5

The procedure is as in Example 1, with 0.7 g of Resomer® instead of 0.5 g of Resomer® RG 858 756 is used.

Example 6

The procedure is as in Example 1, but instead of a 2% polyvinyl alcohol solution (Molecular weight 9000-10000, Aldrich) 25 ml of a 2% Synperonic P 85 solution are given.

Example 7

The procedure is as in Example 1, but instead of a 2% polyvinyl alcohol solution (Molecular weight 9000-10000, Aldrich) 25 ml of a 2% Synperonic F 68 solution are given.

Example 8

The procedure is as in Example 1, but instead of a 2% polyvinyl alcohol solution (Molecular weight 9000-10000, Aldrich) 25 ml of a 2% Tween 20 solution become.

Example 9

The procedure is as in Example 1, but instead of a 2% polyvinyl alcohol solution (Molecular weight 9000-10000, Aldrich) 25 ml of a 2% Brij 96 solution become.

Example 10

The procedure is as in Example 1, but instead of a 2% polyvinyl alcohol solution (Molecular weight 9000-10000, Aldrich) 25 ml of a 2% Brij 35 solution become.  

Example 11

A microporous glass membrane, pore size 1.1 µm (Ashai Glass Co. (Tokyo, Japan) in the "" small system "membrane emulsification apparatus" (Department of Chemistry, Industrial Research Institute of Miazaki Prefeeture (Miyazaki-city, Japan)). A solution consisting of 0.5% [w / v] Resomer® RG 502 and 0.1% [w / v] cyproterone acetate pressed (pressure 24 kPa) and in a circulating 0.5% polyvinyl alcohol solution (molecular weight 9000-10000, Aldrich) and stabilized. The resulting O / W emulsion is transferred to a 500 ml three-necked flask and stirred by means of a KPG stirrer. The organic solvent mixture is then below 20 ° C. removed by applying a vacuum (900 mbar), nitrogen or air introduction. To For 5 hours, the suspension is washed with 5 L of water or an aqueous solution (i.e. from Excess active ingredient and residual solvent exempt) and to a desired Suspension volume concentrated. Advantage is the use of a "cross flow" filtration, for example a Sartocon Mini® (Sartorlus AG, Göttingen) system with one Polyolefin membrane (cutoff 0.2 µm). The solvent and almost emulsifier free Suspension can be made with a croprotector (for example with a sugar, sugar alcohol or polyvinylpyrrolidone derivative) are added and is frozen and freeze-dried.

Contains the lyophilisate resuspended with water or with an aqueous solution surprisingly, microparticles with a cyproterone content of 16.3% (Cyproterone mass * 100 / Cyproterone mass + polymer mass). 99% of all microparticles are smaller than 3 µm and larger than 1.5 µm.

Example 12

A microporous glass membrane, pore size 2.4 µm (Ashai Glass Co. (Tokyo, Japan) in the "" small system "membrane emulsion apparatus" (Department of Chemistry, Industrial Research Institute of Mlazaki Prefecture (Miyazaki-city, Japan)). A solution consisting of 0.5% [w / v] Resomer® RG 502 and 0.1% [w / v] cyproterone acetate pressed (pressure 20 kPa) and in a circulating 0.5% polyvinyl alcohol solution (molecular weight 9000-10000, Aldrich) and stabilized. The resulting O / W emulsion is transferred to a 500 ml three-necked flask and stirred by means of a KPG stirrer. The organic solvent mixture is then below 20 ° C. removed by applying a vacuum (900 mbar), nitrogen or air introduction. To For 5 hours, the suspension is washed with 5 L of water or an aqueous solution (i.e. from Excess active ingredient and residual solvent exempt) and to a desired Suspension volume concentrated. The use of a "cross flow" filtration is advantageous, for example a Sartocon Mini® (Sartorius AG, Göttingen) system with one  Polyolefin membrane (cutoff 0.2 µm). The solvent and almost emulsifier free Suspension can be made with a croprotector (for example with a sugar, sugar alcohol or polyvinylpyrrolidone derivative) are added and is frozen and freeze-dried.

Contains the lyophilisate resuspended with water or with an aqueous solution surprisingly, microparticles with a cyproterone content of 16.3% (Cyproterone mass * 100 / Cyproterone mass + polymer mass). 99% of all microparticles are smaller than 4.5 µm and larger than 2.7 µm.

Claims (4)

1. Microparticles containing active ingredient, characterized in that

• a) as active ingredient cyproterone acetate (21-acetoxy-6-chloro-1,2α-methylene-4,6, - pregnadiene-3,20-dione), chloromadinone acetate (17α-acetoxy-6-chloro-4,6-pregnadiene- 3,20-dione) or 17α-propylmesterolone (17β-hydroxy-lα methyl-17α-M-propyl-5α-androsten-3-one),
• b) the wall material of the microparticle consists of biodegradable, synthetic polymers of polyesters from α, β or γ hydroxycarboxylic acids or of block copolymers of polyesters of α, β, γ hydroxycarboxylic acids and linear or star polyethylene glycols,
• c) the microparticles have a diameter of approximately 0.5 μm to approximately 20 μm.

2. Use of microparticles according to claim 1 for the production of a Drug. 3. Use of microparticles according to claim 1 for producing a Medicinal product for the treatment of androgen-dependent diseases. 4. Use of microparticles according to claim 1 for producing a Lyophilisate, a reconstituted lyophilisate or a suspension, a lotion, a gel or ointment for the treatment of androgen-dependent diseases.