WO2014190898A1

WO2014190898A1 - Preparation of isothiocyanate compounds

Info

Publication number: WO2014190898A1
Application number: PCT/CN2014/078577
Authority: WO
Inventors: 程景才; 顾国林; 王永霞
Original assignee: Cheng Jingcai
Priority date: 2013-05-27
Filing date: 2014-05-27
Publication date: 2014-12-04
Also published as: CN104173272A; CN104173272B; CN105358130A; CN105358130B

Abstract

Disclosed is a sustained-release preparation or capsule of isothiocyanate compounds or derivatives thereof, the sustained-release preparation containing (a) a therapeutically effective amount of isothiocyanate compounds or derivatives thereof; (b) a pharmaceutically acceptable carrier, and the capsule containing a capsule shell and a pharmaceutical composition consisting of components (a) and (b) inside the capsule shell. The sustained-release preparation is stable and has a good compatibility and sustained-release effect; the capsule significantly improves the stability of the drug, and masks the smell of the isothiocyanate compounds and reduces irritation.

Description

Isothiocyanate compound preparation

Technical field

The present invention is in the field of pharmaceutical preparations, and in particular, the present invention relates to a preparation of an isothiocyanate compound or a derivative thereof. Background technique

PCT Application W02007/056941 (Application of isothiocyanate compounds in prostate diseases and skin cancers) The role of isothiocyanate compounds in the treatment and prevention of prostate diseases has been reported.

Studies have shown that isothiocyanate compounds have short half-lives in humans and are fast metabolizing and excreting drugs. Therefore, in the form of an ordinary preparation, the patient needs to take a plurality of medications to maintain the required blood concentration, and the therapeutic effect of the desired condition can be achieved, which brings inconvenience. Prostatic hyperplasia is a chronic disease in the elderly and requires long-term medication. In order to facilitate the administration of the elderly and improve the compliance of the medication, it is necessary to develop a sustained release dosage form of such a compound to meet the above requirements.

In the clinical application, the sustained-release preparation has the advantages of low administration frequency, convenient administration, complete absorption, small fluctuation of blood drug concentration, less toxic side effects, less stimulation to the gastrointestinal tract, and good patient compliance. However, isothiocyanate compounds are very active. In the isothiocyanate compounds (ITCs), C in _N=C=S has high electrophilicity and can be nucleophilic with many nucleophiles. Addition reactions, such as amino, hydroxy, thiol, β-carbonyl, carboxylic acid and other nucleophilic groups, will undergo nucleophilic addition reaction with ITCs to form the corresponding thiourea, and many existing pharmaceutically available The accepted pharmaceutical excipients all have the above groups. ITCs can also react with other ingredients such as proteins, amino acids, ethanol, and additives, resulting in reduced levels of major drugs and impurities. At the same time, ITCs are volatile, have poor moldability and solubility, and are difficult to produce stable, commercially available sustained release preparations.

On the other hand, due to the very active nature of such compounds, such compounds are also susceptible to environmental factors such as moisture, temperature, air, light, etc., thereby affecting the stability of the formulation. In addition, such compounds are susceptible to volatilization, irritating odor, and poor formability, making it difficult to produce stable, commercially available formulations. Summary of the invention

An object of the present invention is to provide a sustained release preparation of a stable isothiocyanate compound or a derivative thereof.

Another object of the present invention is to provide a capsule of an isothiocyanate compound or a derivative thereof having better stability. In a first aspect of the invention, there is provided a formulation of an isothiocyanate compound or a derivative thereof, the preparation comprising:

(a) a therapeutically effective amount of an active ingredient, which is an isothiocyanate compound or a derivative thereof;

(b) a pharmaceutically acceptable carrier;

And the preparation is a sustained release preparation or a controlled release preparation.

According to a second aspect of the present invention, there is provided a preparation of an isothiocyanate compound or a derivative thereof, characterized in that the preparation is a capsule, and the capsule comprises: a capsule shell, and is placed in a capsule a pharmaceutical composition inside the shell, And the pharmaceutical composition comprises:

(b) a pharmaceutically acceptable carrier.

In another preferred embodiment, the active ingredient of the sustained release preparation or capsule is an isothiocyanate compound represented by the formula (I) or a derivative represented by the formula (Π):

A-NCS ( I)

In formula I:

NCS is an isothiocyanate group;

A is one: ^! ^ or one. !^!^!^, where

X is -(CH ₂ ;> _n -, n is an integer from 0 to 6;

! ^ is methyl, tert-butyl, isopropyl, methylthio, methoxy, allyl, methallyl, cyclohexyl, methylsulfinyl, naphthyl, methylcyclohexyl, morpholine Base, diethylamino, benzoyl, ethoxycarbonyl, tert-octyl, chlorine atom, trimethylsilyl, substituted or unsubstituted phenyl;

The term "substituted" means that one or more H groups in the group are substituted with a substituent selected from the group consisting of: a halogen atom, a methyl group, a bromomethyl group, an ethyl group, a methoxy group, a nitro group, an azide group, Trifluoromethyl, difluoromethoxy, methylthio, cyano, trifluoromethoxy, trifluoromethylthio, tert-butoxycarbonyl, ethoxycarbonyl;

R ₂ , R ₃ , and R ₄ are each independently H, phenyl or d. ₃ fluorenyl;

H S

^A "N"C- R ₅ (式_π)

In formula II:

As defined in Equation I;

H S

R ₅ is hydrogen or a group derived from the following compound through a sulfur atom bonded to a carbon atom of -NC-: N-acetylcysteine, glutathione, cysteine (d. ₆ alkyl) ester , cysteinyl amino acid and cysteinyl amino acid (d. ₆ decyl) ester. In another preferred embodiment, the isothiocyanate compound or derivative thereof is derived from: an animal or plant, chemical synthesis or semi-chemical synthesis.

In another preferred embodiment, the isothiocyanate compound or a derivative thereof is selected from one or more of the group consisting of: ethyl phenyl isothiocyanate, cyclohexyl isothiocyanate, 4 -methoxybenzyl isothiocyanate, 4-chlorobenzyl isothiocyanate, 3-phenylpropyl isothiocyanate, 4-phenylbutyl isothiocyanate, 6-phenylhexyl isosulfide Cyanate ester, triphenylmethyl isothiocyanate, 1-isothiocyanate-4-methanesulfonyl butyl hydrazine (rhodium sulfonium sulfonate), α-methyl benzyl isothiocyanate, isothiocyanate Hexyl ester, methylcyclohexyl isothiocyanate, 1-naphthyl isothiocyanate, 2-chlorophenyl isothiocyanate, 2-bromophenyl isothiocyanate, 3-chlorophenyl iso Thiocyanate, 3-bromophenyl isothiocyanate, 3-nitrophenyl isothiocyanate, 4-azidophenyl isothiocyanate, 4-fluorophenyl isothiocyanate, 4-chlorophenyl isothiocyanate, 4-bromophenyl isothiocyanate, 4-nitrophenyl isothiocyanate, ethoxycarbonyl isothiocyanate, tert-octyl isothiocyanate Ester, p-toluene isothiocyanate, benzoyl isothiocyanate, o-toluene isothiocyanate, m-toluene isothiocyanate, 2,3,4-Trifluorophenyl isothiocyanate, 2,5-dimethoxyphenyl isothiocyanate, 2-(4-morpholine)ethyl isothiocyanate, 2- (trifluoromethyl)phenyl isothiocyanate, 2-(difluoromethoxy)phenyl isothiocyanate, 2-(methylthio)phenyl isothiocyanate, 2-fluoro- 5-(Trifluoromethyl)phenyl isothiocyanate, 3,5-bis(trifluoromethyl)phenyl isothiocyanate, 3-(4-morpholinyl;)propyl isothiocyanate Acid ester, 3-(trifluoromethyl)phenyl isothiocyanate, 3-(diethylamino)propyl isothiocyanate, 3-(methylthio)propyl isothiocyanate, 3- (A Thio)phenyl isothiocyanate, 3-cyanophenyl isothiocyanate, 4-(trifluoromethyl)phenyl isothiocyanate, 4-(trifluoromethoxy)phenyl Isothiocyanate, 4-(trifluoromethylthio)phenyl isothiocyanate, 4-(difluoromethoxy)phenyl isothiocyanate, 4-(methylthio)phenyl iso Thiocyanate, 4-cyanophenyl isothiocyanate, 4-bromo-2-fluorophenyl isothiocyanate, 4-methoxyphenyl isothiocyanate, methallyl Isothiocyanate, α-methylbenzyl isothiocyanate, ethyl 2-(4-isothiocyanato)toluenesulfonate, 2-chloroethyl isothiocyanate, isothiocyanate (2-fluorophenyl) ester, (3-fluorophenyl) isothiocyanate, 2-phenylethyl isothiocyanate, butyl isothiocyanate, trimethylsilyl isothiocyanate, isothiocyanate Triphenylmethyl acrylate, propyl isothiocyanate, ethyl isothiocyanate, t-butyl isothiocyanate, isopropyl isothiocyanate, allyl isothiocyanate, isothiocyanate Methyl ester, phenylethyl isothiocyanate, benzyl isothiocyanate, phenyl isothiocyanate, phenyl 2,4,5-trichloroisothiocyanate, 2,4,6-trichloro Phenyl thiocyanate, 2,4-difluoroisosulfide Phenyl cyanate, phenyl 2,5-difluoroisothiocyanate, phenyl 2,6-difluoroisothiocyanate, phenyl 2,6-dimethylisothiocyanate, 2-ethyliso Phenyl thiocyanate, phenyl 2-chloro-4-nitroisothiocyanate, phenyl 3-methoxyisothiocyanate, phenyl 4-(bromomethyl)isothiocyanate, 4-B Phenyl isothiocyanate, phenyl 5-chloro-2-methylisothiocyanate, 1 ,4-dithioisocyanate butyl hydrazine, 2-chloro-5-(trifluoromethyl)isothiocyanate benzene Ester, phenyl 2-methoxy-4-nitroisothiocyanate, phenyl 3,4,5-trimethoxyisothiocyanate, 3-(trifluoromethylthio;) phenyl isothiocyanate Ester, 4-chloro-3-(trifluoromethyl)isothiocyanate, 4-methyl-3-(trifluoromethyl)isothiocyanate, 2,3-dichlorophenyl Thiocyanate, 2,4-dichlorophenylisothiocyanate, 2,5-dichlorophenylisothiocyanate, 2,6-dichlorophenylisothiocyanate , 2-(4-chlorophenyl)ethyl isothiocyanate, 2-(ethoxycarbonyl)phenylisothiocyanate, 2-methoxy-5-methylphenylisosulfide Cyanate, 2-methoxyphenyl thioisocyanate, 2-formyloxyethyl thioisocyanate, 3,4-dichloro Isothiothiocyanate, 3,5-dichlorophenylisothiocyanate, 3-(methylthio)phenylisocyanate, 4-(methylthio)phenylisocyanate, 4-trifluoro Methylthiophenyl isocyanate, 4-fluoro-3-(trifluoromethyl)phenylisothiocyanate, 4-fluoro-3-(trifluoromethyl)phenylisothiocyanate, 4-iodophenylisothiocyanate, tert-butyl 3-isothiocyanatobenzoate, tert-butyl 4-isothiocyanatobenzoate, or oxime-acetyl of each of the above isothiocyanate compounds Cysteine adduct.

Preferably selected from one or more of the group consisting of: phenethyl isothiocyanate, allyl isothiocyanate, benzyl isothiocyanate, phenyl isothiocyanate, Ethyl phenyl isothiocyanate, cyclohexyl isothiocyanate, 4-methoxybenzyl isothiocyanate, 4-chlorobenzyl isothiocyanate, 3-phenylpropyl isothiocyanate Ester, 4-phenylbutyl isothiocyanate, 6-phenylhexyl isothiocyanate, triphenylmethyl isothiocyanate, sulfonium sulfonate, or hydrazine of the above various isothiocyanate compounds - Acetylcysteine adduct.

More preferably selected from one or more of the following groups: phenethyl isothiocyanate, 4-chlorobenzyl isothiocyanate, phenylpropyl isothiocyanate, 3-phenylpropyl iso Thiocyanate, 6-phenylhexyl isothiocyanate, 4-phenylbutyl isothiocyanate, triphenylmethyl isothiocyanate, sulfonium sulfonate, or each of the above isothiocyanate compounds Ν-acetylcysteine adduct.

In another preferred embodiment, the isothiocyanate compound or a derivative thereof is selected from the group consisting of phenethyl isothiocyanate, benzyl isothiocyanate, allyl isothiocyanate. Ester, 4-chlorobenzyl isothiocyanate, phenylpropyl isothiocyanate, sulfonium thiocyanate, phenethyl isothiocyanate-indole-acetylcysteine adduct, or a combination thereof.

In another preferred embodiment, the isothiocyanate compound or derivative is derived from: an animal or plant, chemical synthesis or semi-synthesis. In another preferred embodiment, when the preparation is a sustained release preparation, the preparation includes a slow release material and/or a biodegradable polymer material, and the controlled release material is selected from the group consisting of: wax Or a grease-based material, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, carbomer, sodium alginate, chitin, polyethylene, or a combination thereof; said biodegradable polymer material selected From the next group: polysaccharides, proteins, polylactic acid, lactic acid and hydroxyl Copolymer of acetic acid, polylactic acid-polyethylene glycol copolymer, polylactide-polyethylene glycol copolymer, polyhydroxyalkanoate, polyhydroxybutyrate, or a combination thereof.

In another preferred embodiment, the wax or fat-based material is selected from the group consisting of glyceryl behenate, glyceryl monostearate, polyethylene glycol monostearate, hydrogenated castor oil, hydrogenated vegetable oil , paraffin, beeswax, microcrystalline wax, carnauba wax, wax, wax, insect white wax, cetyl, stearic acid, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cetyl alcohol ester wax, medium chain Oil, soybean oil, olive oil, corn oil, or a combination thereof;

In another preferred embodiment, the controlled release material is used in an amount of 5 to 90% by weight, preferably 10 to 70% by weight based on the total preparation;

The biodegradable polymer material is used in an amount of from 0 to 95% by weight, preferably from 10 to 85% by weight based on the total weight of the preparation. In another preferred embodiment, the capsule is in a form selected from the group consisting of hard capsules, soft capsules, immediate release capsules, controlled release capsules, enteric capsules, stomach soluble capsules, colon Target capsules.

In another preferred embodiment, the pharmaceutical composition is in a form selected from the group consisting of powders, granules, pellets, microspheres, tablets, semi-solids, liquids, or combinations thereof.

In another preferred embodiment, the capsule shell is selected from the group consisting of a gelatin capsule shell, a plant capsule shell, a stomach-soluble capsule shell, an enteric capsule shell, and a colon enteric capsule shell.

In another preferred embodiment, the plant capsule shell is selected from the group consisting of methylcellulose capsule shell, hydroxypropylmethylcellulose capsule shell, ethyl cellulose benzoate capsule shell, starch capsule shell, and pullulan Polysaccharide capsule shell, seaweed polysaccharide capsule shell, carboxymethyl konjac glucomannan capsule shell.

In another preferred embodiment, the formulation further comprises one or more components selected from the group consisting of diluents, adsorbents, solubilizers, binders, disintegrants, and optional lubricants.

In another preferred embodiment, the sustained release formulation has one or more characteristics selected from the group consisting of:

(i) The diluent is selected from the group consisting of glucose, fructose, lactose, maltose, trehalose, sorbitol, mannitol, maltitol, maltodextrin, powdered sugar, dextrin, starch, pregelatinized starch, Microcrystalline cellulose, calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, magnesium carbonate, magnesium oxide, stearic acid palmitate, or a combination thereof; preferred are: lactose, mannitol, dextrin, starch , pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, or a combination thereof.

(ii) The adsorbent is selected from the group consisting of lactose, mannitol, dextrin, cyclodextrin, starch, pregelatinized starch, microcrystalline cellulose, powdered cellulose, calcium hydrogen phosphate, sodium chloride, Calcium sulphate, calcium carbonate, magnesium aluminum silicate, micronized silica gel, kaolin, or a combination thereof; preferred are: lactose, pregelatinized starch, calcium hydrogen phosphate, calcium sulfate, magnesium aluminum silicate, micronized silica gel, white clay, Or a combination thereof.

(iii) The solubilizer is selected from the group consisting of: povidone, crospovidone, polyethylene glycol, poloxamer, sodium decyl sulfate, benzyl benzoate, cyclodextrin, egg Phospholipids, polyoxyethylene decyl ethers, polyoxyethylene castor oil derivatives, polysorbates, fatty acid sorbitan, polyoxyethylene stearate, sucrose esters, or combinations thereof; preferred are: povidone, cross-linking Povidone, polyethylene glycol, poloxamer, sodium dodecyl sulfate, polyoxyethylene castor oil derivatives, or a combination thereof.

(iv) The binder is selected from the group consisting of povidone, gelatin, polyethylene glycol, polyoxyethylene, sucrose, chitosan, dextran, sodium alginate, maltodextrin, starch, fiber A derivative, corn mash, or a combination thereof; preferred are: povidone, gelatin, polyethylene glycol, sucrose, starch, cellulose derivatives, or a combination thereof.

The lubricant of (V) is selected from the group consisting of stearic acid, magnesium stearate, zinc stearate, palmitate stearate, Glyceryl monostearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, magnesium silicate, magnesium trisilicate, sodium hard fumarate, or combinations thereof; preferably : magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, or a combination thereof.

In another preferred embodiment, the capsule further has one or more characteristics selected from the group consisting of:

(i) The diluent is selected from the group consisting of glucose, maltose, maltitol, maltodextrin, lactose, fructose, powdered sugar, chitin, starch, pregelatinized starch, dextrin, mannitol, sorbitol, Calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, magnesium carbonate, magnesium oxide, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyethylene, carbomer, hard Glyceryl palmitate, trehalose, sodium alginate, glyceryl behenate, glyceryl monostearate, polyethylene glycol monostearate, hydrogenated castor oil, hydrogenated vegetable oil, paraffin wax, beeswax, microcrystalline Wax, carnauba wax, wax, wax, insect white wax, cetyl, stearic acid, cetyl alcohol, cetyl alcohol wax, stearyl alcohol, cetostearyl alcohol, medium chain oil, soybean oil, olive oil , corn oil, or a combination thereof;

Preferred are: lactose, mannitol, starch, pregelatinized starch, dextrin, calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, microcrystalline cellulose, methyl cellulose, ethyl cellulose, Kappa M, chitin, behenic acid glyceride, hydrogenated castor oil, hydrogenated vegetable oil, carnauba wax, stearic acid, medium chain oil, soybean oil, olive oil, corn oil, or a combination thereof.

(ii) The adsorbent is selected from the group consisting of lactose, mannitol, starch, pregelatinized starch, dextrin, cyclodextrin, calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, kaolin, silicon. Magnesium aluminate, microcrystalline cellulose, micronized silica gel, powdered cellulose, or a combination thereof;

Preferred are: lactose, pregelatinized starch, calcium hydrogen phosphate, calcium sulfate, micronized silica gel, kaolin, magnesium aluminum silicate, or combinations thereof.

(iii) The solubilizer is selected from the group consisting of: povidone, crospovidone, polyethylene glycol, poloxamer, sodium decyl sulfate, benzyl benzoate, cyclodextrin, egg a phospholipid, a polyoxyethylene methyl ether, a polyoxyethylene castor oil derivative, a polysorbate, a fatty acid sorbitan, a polyoxyethylene stearate, a sucrose ester, or a combination thereof;

Preferred are: povidone, crospovidone, polyethylene glycol, poloxamer, sodium dodecyl sulfate, polyoxyethylene castor oil derivatives, or combinations thereof.

(iv) The binder is selected from the group consisting of starch, cellulose derivatives, povidone, gelatin, polyethylene glycol, sucrose, maltodextrin, sodium alginate, chitosan, dextran, Polyoxyethylene, corn mash, or a combination thereof;

Preferred are: starch, cellulose derivative, povidone, gelatin, polyethylene glycol, sucrose, or a combination thereof; (V) the disintegrant is selected from the group consisting of starch, sodium carboxymethyl starch, Carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, or a combination thereof;

Preferred are: starch, sodium carboxymethyl starch, croscarmellose sodium, or a combination thereof.

(vi) The lubricant is selected from the group consisting of magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, palmitic palmitate, monostearic acid. a glyceride, magnesium silicate, magnesium trisilicate, sodium hard fumarate, stearic acid, zinc stearate, or a combination thereof;

Preferred are: magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, or a combination thereof.

In another preferred embodiment, the preparation further comprises an antioxidant, preferably, the antioxidant is VE or

VC.

In another preferred embodiment, the capsule is a sustained release preparation, a controlled release preparation, or a non-sustained release preparation. In another preferred embodiment, the formulation further has one or more of the following characteristics:

The diluent and the adsorbent account for 0-90% by weight of the total weight of the preparation;

The solubilizer accounts for 0-50% by weight of the total weight of the preparation;

The binder accounts for 0-50% by weight of the total weight of the preparation;

The disintegrant accounts for 0-10% by weight of the total weight of the preparation;

The lubricant is 0-10% by weight based on the total weight of the formulation.

In another preferred embodiment, the sustained release preparation comprises, in addition to the active ingredient, one or more of the following components: a slow release material, the controlled release material comprising 10 to 70% by weight of the total weight of the preparation. Or, the biodegradable polymer material, the degradable polymer material accounts for 10-85% by weight, preferably 10-70% by weight of the total weight of the preparation;

The diluent and the adsorbent, the diluent and the adsorbent account for 20-80% by weight of the total weight of the preparation;

a solubilizing agent, the solubilizing agent is 5-20% by weight based on the total weight of the preparation;

a binder, the binder comprising 5-10% by weight of the total weight of the formulation;

The lubricant, the lubricant, is from 0.1 to 5% by weight based on the total weight of the formulation.

In another preferred embodiment, the sustained release preparation has the following characteristics:

The formulation has a 1 hour release of 45%, preferably 40%;

The formulation has an 8-hour release of 70%, preferably 80%.

Or the formulation has the following characteristics:

The sustained release preparation has a 1 day release of 45%, preferably 40%;

The sustained release preparation has a 28 day release of 70%, preferably 80%.

In another preferred embodiment, the sustained release preparation forms are tablets, hard capsules, soft capsules, granules, dropping pills, pellets, microspheres, microcapsules, polymer micelles, sustained release tablets, and capsules. , injection or implant.

In another preferred embodiment, the sustained release preparation form is selected from the group consisting of: skeleton type controlled release granules (or pellets, pellets, dropping pills), membrane controlled release type controlled release granules (or pellets, pellets, Drop pills); and skeleton type controlled release tablets.

In another preferred embodiment, the capsule comprises, in addition to the therapeutically effective amount of the active ingredient, one or more of the following components:

The binder, the binder accounts for 5-10% by weight of the total weight of the preparation;

a 5% by weight; and the disintegrating agent is 0. l_5wt%;

L-5wt%。 The lubricant, the total weight of the formulation is 0. l-5wt%.

According to a third aspect of the invention, there is provided a method of preparing a sustained release preparation according to the first aspect of the invention, the method comprising the steps of:

Providing an active ingredient, the active ingredient being an isothiocyanate compound or a derivative thereof;

Melting the controlled release material and mixing with the active ingredient to form a first dispersion;

The first dispersion is mixed with other excipients and formulated into a formulation.

According to a fourth aspect of the present invention, there is provided a sustained release controlled injection or implant of an isothiocyanate compound or a derivative thereof.

In another preferred embodiment, the preparation further comprises a biodegradable polymer material selected from the group consisting of polysaccharides, proteins, polylactic acid, copolymers of lactic acid and glycolic acid, and polylactic acid-polyethylene glycol copolymerization. Polylactide-polyethyl a diol copolymer, a polyhydroxyalkanoate, a polyhydroxybutyrate, or a combination thereof; preferably: chitosan and blends thereof, cyclodextrin and its derivatives, albumin, zein, polylactic acid And a copolymer of lactic acid and glycolic acid, a polylactic acid-polyethylene glycol copolymer, a polylactide-polyethylene glycol copolymer, a polyhydroxyalkanoate, a polyhydroxybutyrate, or a combination thereof.

In another preferred embodiment, the route of administration of the formulation is selected from the group consisting of intravenous, intramuscular, subcutaneous, intradermal, intratumoral, paratumor, or a combination thereof.

In another preferred embodiment, the formulation is an implant, preferably a capsule-type implant, or an injectable implant. In another preferred embodiment, the formulation is prepared by the following method:

Under aseptic conditions, the active ingredient and the biodegradable polymer material are mixed and melted, and then extruded into a strip shape through a porous device. The strip is generally about 1 mm in diameter, and is cut into a length containing a single dose of the drug, and then directly loaded. Specially made disposable syringes.

According to a fifth aspect of the invention, there is provided a use of a preparation according to the first aspect of the invention for the treatment or prevention of a tumor, a prostate disease, a skin disease, alopecia, inflammation.

In another preferred embodiment, the tumor comprises liver cancer, gastric cancer, lung cancer, breast cancer, esophageal cancer, small intestine cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, melanoma, neuroblastoma and the like.

In another preferred embodiment, the prostate disease includes benign prostatic hyperplasia, prostatitis, and prostate cancer. It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with one another to form a new or preferred technical solution. Due to space limitations, we will not repeat them here. detailed description

The inventors have extensively and intensively studied and unexpectedly discovered that wax or oily materials, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, carbomer, sodium alginate, chitin, poly Ethylene is highly compatible with isothiocyanate compounds, and such excipients also have an inhibitory effect on the decrease in the content of isothiocyanate compounds in pharmaceutical compositions. Based on the above findings, the inventors prepared a sustained-release preparation of an isothiocyanate compound or a derivative thereof which has a good controlled release effect and good stability.

On the basis of long-term research, the present inventors have found that the isocyanate compound which is easily decomposed into a capsule can effectively protect the isothiocyanate compound or its derivative from the environment. The influence of water, temperature, air, and inhibition of volatilization significantly improves the stability of the drug while masking the odor of the compound and reducing the irritancy, and solves the problem of poor stability such as tablets or pills. Based on the above findings, the inventors prepared a capsule which released a good and stable isothiocyanate compound or a derivative thereof. the term

As used herein, the term "sustained release" means sustained release or controlled release, i.e., the active ingredient can be sustainedly released over a prolonged period of time after administration of the formulation. In the present invention, a preferred sustained release preparation (or a controlled release preparation) can be continuously released within 0.5 to 8 hours.

The term "wax or oil-based material" means a pharmaceutically acceptable wax drug carrier, or a lipid drug carrier such as carnauba wax, glyceryl behenate or the like. Isothiocyanate

As used herein, "active ingredient" or "isothiocyanate compound or derivative thereof" and "isothiocyanate compound" are used interchangeably and mean isothiocyanate as shown in formula (I). An acid ester compound, or a derivative of an isothiocyanate compound represented by the formula (Π):

A-NCS ( I )

In formula I:

NCS is an isothiocyanate group;

A is a 1^ or a 0? ₂ 3⁄4, where

X is - ((3⁄4)„-, n is an integer from 0-6;

Is methyl, tert-butyl, isopropyl, methylthio, methoxy, allyl, methallyl, cyclohexyl, methylsulfinyl, naphthyl, methylcyclohexyl, morpholinyl , diethylamino, benzoyl, ethoxycarbonyl, tert-octyl, chlorine atom, trimethylsilyl, substituted or unsubstituted phenyl;

R ₂ , R ₃ and R ₄ are each independently H, phenyl or d ₃ fluorenyl.

(Formula II)

In formula I I:

A is as defined in formula I;

a group derived from hydrogen or a carbon atom bonded to a carbon atom through a sulfur atom: N-acetylcysteine, glutathione, cysteine (d- ₆ alkyl) ester, cysteine An aminoacyl amino acid and a cysteinyl amino acid (d- ₆ alkyl) ester.

In another preferred embodiment, the amino acid is selected from the group consisting of glycine, glutamic acid, serine, alanine, or methionine. A preferred class of isothiocyanate compounds or derivatives thereof include, but are not limited to, ethyl phenyl isothiocyanate, cyclohexyl isothiocyanate, 4-methoxybenzyl isothiocyanate, 4-chlorobenzyl isothiocyanate, 3-phenylpropyl isothiocyanate, 4-phenylbutyl isothiocyanate, 6-phenylhexyl isothiocyanate, triphenylmethyl isothiocyanate Acid ester, 1-isothiocyanate-4-methanesulfonyl butyl hydrazine (rhodium sulfonium sulfonate), α-methyl benzyl isothiocyanate, hexyl isothiocyanate, methylcyclohexyl isothiocyanate , 1-naphthyl isothiocyanate, 2-chlorophenyl isothiocyanate, 2-bromophenyl isothiocyanate, 3-chlorophenyl isothiocyanate, 3-bromophenyl isothiocyanate Cyanate ester, 3-nitrophenyl isothiocyanate, 4-azidophenyl isothiocyanate, 4-fluorophenyl isothiocyanate, 4-chlorophenyl isothiocyanate, 4 -Bromophenyl isothiocyanate, 4-nitrophenyl isothiocyanate, ethoxycarbonyl isothiocyanate, tert-octyl isothiocyanate, p-toluene isothiocyanate, benzo Acyl isothiocyanate, o-toluene isothiocyanate, m-toluene isothiocyanate, 2,3,4-trifluorophenyl isosulfide Acid ester, 2,5-dimethoxyphenyl isothiocyanate, 2-(4-morpholine)ethyl isothiocyanate, 2-(trifluoromethyl)phenyl isothiocyanate , 2-(difluoromethoxy) phenyl isothiocyanate, 2-(methylthio;)phenyl isothiocyanate, 2-fluoro-5-(trifluoromethyl)phenyl Thiocyanate, 3,5-bis(trifluoromethyl)phenyl isothiocyanate, 3-(4-morpholinyl)propyl isothiocyanate, 3-(trifluoromethyl)benzene Isothiocyanate, 3-(diethylamino)propyl isothiocyanate, 3-(methylthio)propyl isothiocyanate, 3-(methylthio)phenyl isothiocyanate Acid ester, 3-cyanophenyl isothiocyanate, 4-(trifluoromethyl)phenyl isothiocyanate, 4-(trifluoromethoxy)phenyl phenyl isothiocyanate, 4 - (Trifluoromethylthio)phenyl isothiocyanate, 4-(difluoromethoxy)phenyl isothiocyanate, 4-(methylthio)benzene Isothiocyanate, 4-cyanophenyl isothiocyanate, 4-bromo-2-fluorophenyl isothiocyanate, 4-methoxyphenyl isothiocyanate, methene Propyl isothiocyanate, α-methylbenzyl isothiocyanate, ethyl 2-(4-isothiocyanatophenoxy)toluenesulfonate, 2-chloroethyl isothiocyanate, isosulfur (2-fluorophenyl) cyanate, (3-fluorophenyl) isothiocyanate, 2-phenylethyl isothiocyanate, butyl isothiocyanate, trimethylsilyl isothiocyanate, different Triphenylmethyl thiocyanate, propyl isothiocyanate, ethyl isothiocyanate, t-butyl isothiocyanate, isopropyl isothiocyanate, allyl isothiocyanate, isosulfur Methyl cyanate, phenylethyl isothiocyanate, benzyl isothiocyanate, phenyl isothiocyanate, phenyl 2,4,5-trichloroisothiocyanate, 2,4,6-three Phenyl chloroisothiocyanate, phenyl 2,4-difluoroisothiocyanate, phenyl 2,5-difluoroisothiocyanate, phenyl 2,6-difluoroisothiocyanate, 2,6 - phenyl dimethyl isothiocyanate, phenyl 2-ethylisothiocyanate, phenyl 2-chloro-4-nitroisothiocyanate, phenyl 3-methoxyisothiocyanate, 4 - (Bromomethyl) phenyl isothiocyanate, 4-ethyliso Phenyl thiocyanate, phenyl 5-chloro-2-methylisothiocyanate, 1,4-dithioisocyanate butyl hydrazine, 2-chloro-5-(trifluoromethyl)isothiocyanate, Phenyl 2-methoxy-4-nitroisothiocyanate, phenyl 3,4,5-trimethoxyisothiocyanate, 3-(trifluoromethylthio;)phenylphenyl isothiocyanate, 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate, 4-methyl-3-(trifluoromethyl)isothiocyanate, 2,3-dichlorophenylisothio Cyanate ester, 2,4-dichlorophenyl isothiocyanate, 2,5-dichlorophenyl isothiocyanate, 2,6-dichlorophenyl isothiocyanate, 2 -(4-chlorophenyl)ethylisothiocyanate, 2-(ethoxycarbonyl;)phenylisothiocyanate, 2-methoxy-5-methylphenylisothio Cyanate ester, 2-methoxyphenyl thioisocyanate, 2-methyloxyethyl thioisocyanate, 3,4-dichlorophenyl isothiocyanate, 3,5-dichlorophenyl Isothiocyanate, 3-(methylthio)phenylisocyanate, 4-(methylthio)phenylisocyanate, 4-trifluoromethylthiophenylisocyanate, 4-fluoro-3-(trifluoro) Methyl)phenylisothiocyanate, 4-fluoro-3-(trifluoromethyl)phenyl Thiocyanate, 4-iodophenylisothiocyanate, tert-butyl 3-isothiocyanatobenzoate, tert-butyl 4-isothiocyanatobenzoate, or each of the above isothiocyanates A quinone-acetylcysteine adduct of a compound.

The above isothiocyanate compound or a derivative thereof may be used singly or in combination of two or more kinds. When used in combination, the mass ratio of each compound is not particularly limited on the premise of achieving the therapeutic purpose.

In the present invention, there is no particular limitation on the method for obtaining an isothiocyanate compound or a derivative thereof, for example, it can be extracted from a natural plant such as mustard or radish, and prepared by chemical synthesis or semi-chemical synthesis. Wait. The isothiocyanate compound or a derivative thereof used in the present invention is commercially available, and is commercially available, for example, from Sigma-Aldrich. Sustained release preparation of isothiocyanate compound or derivative thereof

Isothiocyanate compounds or derivatives thereof have been shown to have a good effect in the treatment and prevention of human prostate diseases and various cancers. However, in the form of ordinary preparations, patients need to take multiple medications to maintain the desired The blood concentration can achieve the desired therapeutic effect, which brings a lot of inconvenience to the patient. The properties of the isothiocyanate compounds, such as their active nature, poor solubility and difficulty in molding, make it difficult to prepare into sustained release preparations. The present invention overcomes the problems of active, poor solubility and difficulty in molding of isothiocyanate compounds, and provides a sustained release preparation of an isothiocyanate compound or a derivative thereof, the sustained release preparation containing the treatment An effective amount of an isothiocyanate compound or derivative thereof, a slow release or biodegradable polymer material, and other pharmaceutically acceptable carriers. Wherein, the other carrier includes a diluent, an adsorbent, a solubilizer, a binder, a lubricant, and the like.

The controlled release material suitable for the sustained release preparation of the present invention is a wax or fat material, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, carbomer, sodium alginate, chitin, polyethylene. , or a combination thereof. The above controlled release materials can also be combined with other types of controlled release materials without affecting the stability of the preparation. Preferably, the above controlled release materials include, but are not limited to, glyceryl behenate, glyceryl monostearate, polyethylene glycol monostearate, hydrogenated castor oil, hydrogenated vegetable oil, paraffin wax, beeswax, Microcrystalline wax, carnauba wax, wax, white wax, insect white wax, cetyl wax, stearic acid, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cetyl alcohol ester wax, medium chain oil, soybean oil, Olive oil, corn oil, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, carbomer, sodium alginate, chitin, acrylic, polyethylene, or a combination thereof.

Preferably, the controlled release material is used in an amount of from 5 to 90% by weight, more preferably from 10 to 70% by weight based on the total amount of the preparation.

Biodegradable polymer materials suitable for use in the present invention are polysaccharides, proteins, polylactic acid, copolymers of lactic acid and glycolic acid, polylactic acid-polyethylene glycol copolymers, polylactide-polyethylene glycol copolymers. , a polyhydroxyalkanoate, a polyhydroxybutyrate, or a combination thereof. Preferably, the biodegradable polymer materials mentioned above include, but are not limited to, chitosan and blends thereof, cyclodextrin and its derivatives, albumin, zein, polylactic acid, copolymerization of lactic acid and glycolic acid. , polylactic acid-polyethylene glycol copolymer, polylactide-polyethylene glycol copolymer, polyhydroxyalkanoate, polyhydroxybutyrate, or a combination thereof.

Preferably, the biodegradable polymer material is used in an amount of 0 to 95% by weight based on the total weight of the preparation, preferably

10 - 85wt%.

The diluent is not particularly limited and includes, but is not limited to, glucose, fructose, lactose, maltose, trehalose, sorbitol, mannitol, maltitol, maltodextrin, powdered sugar, dextrin, starch, pre- Gelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, magnesium carbonate, magnesium oxide, stearic acid palmitate, or a combination thereof.

The adsorbent is not particularly limited and includes, but is not limited to, lactose, mannitol, dextrin, cyclodextrin, starch, pregelatinized starch, microcrystalline cellulose, powdered cellulose, calcium hydrogen phosphate, Sodium chloride, calcium sulfate, calcium carbonate, magnesium aluminum silicate, micronized silica gel, white clay, or a combination thereof.

The diluent and the adsorbent may be of the same kind or different kinds, preferably the same substance. Preferably, the diluent and adsorbent are selected from pharmaceutically acceptable components which are less hygroscopic to increase the stability of the formulation.

The solubilizing agent is not particularly limited, and a component capable of increasing the stability of the isothiocyanate compound, such as povidone, crospovidone, polyethylene glycol, poloxamer, or the like, is preferably used. Sodium decyl sulfate, benzyl benzoate, cyclodextrin, lecithin, polyoxyethylene decyl ether, polyoxyethylene castor oil derivative, polysorbate, fatty acid sorbitan, polyoxyethylene stearate, Sucrose ester, or a combination thereof.

The binder is not particularly limited and is preferably selected from the group consisting of povidone, gelatin, polyethylene glycol, polyoxyethylene, sucrose, chitosan, dextran, sodium alginate, maltodextrin. , starch, cellulose derivatives, corn mash, or a combination thereof.

The lubricant is preferably selected from the group consisting of stearic acid, magnesium stearate, zinc stearate, palmitic palmitate, glyceryl monostearate, silica gel, talc, hydrogenated vegetable oil , polyethylene glycols, sodium lauryl sulfate, Magnesium silicate, magnesium trisilicate, sodium hard fumarate, or a combination thereof.

In another preferred embodiment, the formulation further comprises an antioxidant, preferably the antioxidant is VE or vc.

In a preferred embodiment of the invention, the formulation has one or more of the following characteristics:

The binder accounts for 0-50% by weight of the total weight of the preparation;

The lubricant is 0-10% by weight based on the total weight of the formulation.

In another preferred embodiment of the invention, the preparation comprises, in addition to the active ingredient, one or more of the following components:

The controlled release material, the controlled release material accounts for 10-70% by weight of the total weight of the preparation _;

L-5wt%。 The lubricant, the total weight of the formulation is 0. l-5wt%.

Or, the biodegradable polymer material, the degradable polymer material accounts for 10-85 wt% of the total weight of the preparation. The sustained release preparation has a good sustained release property, and in another preferred embodiment, the sustained release preparation has a 1 hour release of 45%, preferably 40%; and the sustained release preparation has an 8-hour release The degree is 70%, preferably 80%. In another preferred embodiment, the sustained release preparation has a 1 day release of 45%, preferably 40%; and the sustained release preparation has a 28 day release of 70%, preferably 80%.

Here, as the isothiocyanate compound or a derivative thereof, any of the isothiocyanate compounds or derivatives thereof as described above can be used. The above isothiocyanate compound or a derivative thereof may be used singly or in combination of two or more. When used in combination, the mass ratio of each compound is not particularly limited as long as the therapeutic purpose is achieved.

In the present invention, there is no particular limitation on the method for obtaining an isothiocyanate compound or a derivative thereof, for example, it can be extracted from a natural plant such as mustard or radish, and prepared by chemical synthesis or semi-chemical synthesis. Wait. The isothiocyanate compound or a derivative thereof used in the present invention is commercially available, and is commercially available, for example, from Sigma-Aldrich.

Preferably, the sustained release preparation is in a form capable of preventing volatilization of the main component, such as granules, tablets, or pelletized capsules, sugar-coated or film-coated tablets. In another preferred embodiment, the sustained release preparation form is selected from the group consisting of: skeleton type controlled release granules (or pellets, pellets, dropping pills), membrane controlled release type controlled release granules (or pellets, pellets, Drop pills); and skeleton type controlled release tablets.

The sustained release preparation can be used for treating or preventing tumors, prostate diseases, hair loss, inflammation, and the like. In another preferred embodiment, the prostate disease includes benign prostatic hyperplasia, prostatitis, and prostate cancer. Capsules of isothiocyanate compounds

Isothiocyanate compounds or derivatives thereof have been shown to have a good effect in the treatment and prevention of human prostate diseases and various cancers. However, isothiocyanate compounds are active, volatile, and irritating. Properties such as odor, poor water solubility, and difficulty in forming determine that it is difficult to prepare a formulation having good stability and good performance. The invention overcomes the problems of active, volatile, irritating odor, poor water solubility and difficulty in forming of isothiocyanate compounds, and provides a capsule of an isothiocyanate compound or a derivative thereof. The capsules include a capsule shell and a pharmaceutical composition.

Wherein the pharmaceutical composition contains a therapeutically effective amount of an isothiocyanate compound or a derivative thereof, and a pharmaceutically acceptable carrier. Among them, the pharmaceutically acceptable carrier includes a diluent, an adsorbent, a solubilizer, a binder, a disintegrant, a lubricant, and the like.

The diluent is not particularly limited and includes, but is not limited to, glucose, maltose, maltitol, maltodextrin, lactose, fructose, powdered sugar, chitin, starch, pregelatinized starch, dextrin, mannitol. , sorbitol, calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, magnesium carbonate, magnesium oxide, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyethylene, card Bom, palmitate stearate, trehalose, sodium alginate, glyceryl behenate, glyceryl monostearate, polyethylene glycol monostearate, hydrogenated castor oil, hydrogenated vegetable oil, paraffin, Beeswax, microcrystalline wax, carnauba wax, chuan wax, white wax, insect white wax, cetyl wax, stearic acid, cetyl alcohol, cetyl alcohol ester wax, stearyl alcohol, hexadecanol, medium chain oil, large Soybean oil, olive oil, corn oil, or a combination thereof;

The adsorbent is not particularly limited and includes, but is not limited to, lactose, mannitol, starch, pregelatinized starch, dextrin, cyclodextrin, calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, White clay, magnesium aluminum silicate, microcrystalline cellulose, microsilica gel, powdered cellulose, or a combination thereof.

The solubilizing agent is not particularly limited, and a component capable of increasing the stability of the isothiocyanate compound or its derivative, such as povidone, crospovidone, polyethylene glycol, poise, is preferably used. Losham, sodium decyl sulfate, benzyl benzoate, cyclodextrin, lecithin, polyoxyethylene decyl ether, polyoxyethylene castor oil derivative, polysorbate, fatty acid sorbitan, stearic acid Oxyethylene vinyl ester, sucrose ester, or a combination thereof; preferred are: povidone, crospovidone, polyethylene glycol, poloxamer, sodium dodecyl sulfate, polyoxyethylene castor oil derivative, Or a combination thereof.

The binder is not particularly limited, and is preferably selected from the group consisting of starch, cellulose derivatives, povidone, gelatin, polyethylene glycol, sucrose, maltodextrin, sodium alginate, chitosan, Dextran, polyoxyethylene, corn mash, or a combination thereof.

The disintegrant is not particularly limited, and is preferably selected from the group consisting of starch, sodium carboxymethyl starch, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, Cross-linked povidone, or a combination thereof.

The lubricant is preferably selected from the group consisting of magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, palmitic palmitate, monostearic acid. One or more of glyceride, magnesium silicate, magnesium trisilicate, sodium hard fumarate, stearic acid, zinc stearate, and the like.

In another preferred embodiment, the capsule further comprises an antioxidant, preferably the antioxidant is VE or VC.

In a preferred embodiment of the invention, the capsule has one or more of the following characteristics:

The binder accounts for 0-50% by weight of the total weight of the preparation;

The lubricant is from 0 to 10% by weight based on the total weight of the formulation. In another preferred embodiment of the invention, the capsule comprises the following components:

An isothiocyanate compound or a derivative thereof;

a solubilizing agent, the solubilizing agent accounts for 5-20% by weight of the total weight of the preparation _;

L-5wt% _; and the disintegrating agent, the total weight of the formulation is 0. l-5wt% _;

L-5wt%。 The lubricant, the total weight of the formulation is 0. l-5wt%.

The type of the isothiocyanate compound or a derivative thereof is not particularly limited, and any of the usual isothiocyanate compounds or derivatives thereof, preferably isothiocyanates as described above, may be used. a compound or a derivative thereof. The above isothiocyanate compound or a derivative thereof may be used singly or in combination of two or more. When used in combination, the mass ratio of each compound is not particularly satisfactory for therapeutic purposes. limit. Preparation method of sustained release preparation

The present invention also provides a process for preparing a sustained release preparation of an isothiocyanate compound or a derivative thereof, the method comprising the steps of:

Providing an isothiocyanate compound or a derivative thereof;

Melting the controlled release material and mixing with the isothiocyanate compound or a derivative thereof to form a first dispersion;

The isothiocyanate compound or a derivative thereof can be produced by a conventional method or can be obtained by a commercially available route.

In another preferred embodiment, the formulation is prepared by the following method:

The active ingredient is mixed and melted with the biodegradable polymer material, and then extruded into a strip shape through a porous device. The strip is generally about 1 mm in diameter, and is cut into a length containing a single dose of the drug, and then directly loaded into a special disposable syringe. in.

The sustained release preparation may be prepared by any conventional techniques known in the art, such as filling capsules, melt agitation, extrusion, spray condensation, centrifugation, etc. to prepare granules or pellets, tableting, coating, and the like. Method for preparing capsule

The present invention also provides a method for preparing a capsule of an isothiocyanate compound or a derivative thereof, the method comprising the steps of:

Providing an isothiocyanate compound or a derivative thereof;

Mixing an adsorbent or diluent with the isothiocyanate compound or a derivative thereof to form a first dispersion; mixing the first dispersion with other excipients, without further processing or further processing into pellets or tablets In a form, it is filled in a capsule to prepare a preparation.

The capsules can be prepared by any of the conventional techniques conventional in the art. The main advantages of the invention include:

The sustained-release preparation of the invention can reduce the frequency of administration, is convenient for administration, and has complete absorption, small fluctuation of blood drug concentration, less toxic and side effects, less stimulation to the gastrointestinal tract, and enhanced patient compliance. It solves the shortcomings of common preparations because the half-life of isothiocyanate compounds in humans is very short, and patients need to take multiple medications to achieve the desired therapeutic effect. In addition, benign prostatic hyperplasia is a chronic disease requiring long-term use of drugs, and most patients with benign prostatic hyperplasia are elderly. The preparation of the present invention enhances the compliance of the elderly with medication.

Further, the sustained-release preparation of the present invention has an unexpected effect in stability. Mainly in two aspects: 1) The preferred excipients of the present invention have good compatibility with isothiocyanate compounds or derivatives thereof; 2) Excipients have a protective effect on the stability of the main drug.

The capsule of the invention can effectively mask the bad odor of the medicine and reduce the irritancy of the medicine; the capsule directly filled in powder, granule, tablet or liquid, disperses quickly in the gastrointestinal fluid, absorbs well, and bioavailability high.

The capsule of the invention can effectively improve the drug stability of the isothiocyanate compound or its derivative, and can prevent the drug from volatilizing, and the drug is not easily deteriorated under the conventional storage conditions, and can also make up for the deficiency of other dosage forms.

In particular, the capsules of the present invention can also be formulated as slow, controlled release or targeted release preparations, such as pellets or pellets, and then coated with polymeric materials of different release rates, as needed. After mixing, it is filled into capsules to prepare various types of capsule preparations such as sustained release and enteric dissolution.

A most preferred formulation of the invention is a sustained release formulation in the form of a capsule. The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer. Unless otherwise stated, the fractions and percentages are parts by weight or percentage by weight. Example 1 : Excipient compatibility test

Method: The isothiocyanate compound and the auxiliary materials are mixed in a certain ratio (the method is simple mixing, melting, etc.). Each excipient is set in parallel with the auxiliary blank group. After preparation, it was placed in a glass container, sealed, and then inspected at 60 ° C, and tested at 0 days, 5 days, and 10 days.

Measurement conditions: The content of isothiocyanate in the mixture was determined by HPLC-UV method, and the impurities in the process were monitored.

Result:

Some of the data are as follows (for the purpose of phenethyl isothiocyanate):

Table 1 Changes in the content of phenethyl isothiocyanate in different excipients

Micro-crystalline wax 102. 1 101. 8 No carnauba wax 100. 8 100. 9 No paraffin wax 101. 2 98. 1 Non-hydrogenated soybean oil 94. 5 92. 3 No hydrogenated castor oil 95. 1 94. 2 No card wave 92. 5 91 Without the data in the above table, the compatibility of the commonly used slow-release materials hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC) with isothiocyanate compounds is not ideal. After being left for a long time, impurities are generated in the preparation, and at the same time, the content of the active pharmaceutical ingredient is largely changed.

When wax or fat materials and ethyl cellulose and carbomer were used as excipients, the content of active pharmaceutical ingredients did not decrease significantly, and no detectable amount of unknown new impurities appeared. Therefore, waxes or fats and materials, as well as ethyl cellulose and carbomer, exhibit significant advantages in the preparation of sustained release pharmaceutical compositions of isothiocyanate compounds or derivatives thereof. Example 2: Excipient stability experiment

Based on the excipient compatibility test of Example 1, the stability protection of different excipients for isothiocyanate compounds was further investigated.

Method: The excipients and isothiocyanate compounds were melted or ground and mixed in a certain ratio. The mixture was placed in a vial and the open mouth was at 60 °C. The HPLC-UV method was used to determine the isothiocyanate in the mixture at different time points. The content of the acid ester compound.

The results are shown in Table 2 to Table 3.

Table 2

table 3

The results of Tables 2 and 3 suggest:

Different excipients have protective effects on the stability of isothiocyanate compounds under the conditions tested, and medium chain oils> bees Wax, microcrystalline wax, palm wax > other excipients; the data of this example show that wax or grease excipients have significant advantages in suppressing the reduction of the content of isothiocyanate compounds relative to other solid diluents. Therefore, the present invention selects the above-mentioned excipients to serve to stabilize the main drug in the prescription. Example 3: Drug sustained release preparations with different excipients

Example 3-1: Preparation of sustained release preparation

Example 3-1-1: Prescription 1

Preparation process: first melt the carnauba wax, then add phenethyl isothiocyanate, mix, add other excipients, mix, pour down on the surface of cold glass, cool, sieve, select 14-20 mesh Granule filling capsules.

Example 3-1-2: Prescription 2

Preparation process: firstly hydrogenated castor oil, then add phenethyl isothiocyanate, mix, pour down on the surface of cold glass, cool, smash through 30 mesh sieve and other auxiliary materials (over 30 mesh fine powder ) Mixing, hot melt extrusion, cutting, giving a diameter of 1 length 2 granules, filling capsules.

Example 3-1-3: Prescription 3

Example 3-1-4: Prescription 4

Component amount (mg)

Phenylethyl isothiocyanate 50

Carbomer 75

Hydrogenated castor oil 75

Lactose 25 Polosham

Preparation process: first melt hydrogenated castor oil, then add phenethyl isothiocyanate, mix, add carbomer, thinner, solubilizer and other auxiliary materials, mix, hot and sieve, take 14-20 Eye pellets.

Example 3-1-5: Prescription 5

Preparation process: First, hydrogenated castor oil is melted, then phenethyl isothiocyanate is added, and after mixing, other auxiliary materials are added, mixed, hot-sifted, and 14-20 mesh pellets are taken.

Example 3-1-6: Prescription 6

Preparation process: first melt the carnauba wax, then add 4-methoxybenzyl isothiocyanate, mix, add other auxiliary materials, mix, pour down on the surface of cold glass, cool, sieve, take 14-20 mesh pellets.

Example 3-1-7: Prescription 7

Preparation process: first melt the carnauba wax, then add benzyl isothiocyanate, mix, add other auxiliary materials, mix, pour down on the surface of cold glass, cool, sieve, take 14-20 mesh Granule filling capsules.

Example 3-1-8: Prescription 8

Preparation process: first melt the carnauba wax, then add phenethyl isothiocyanate-N-acetylcysteine adduct, add other excipients, mix, pour the tile on the surface of the cold glass, cool, pass Sieve, take 14-20 mesh particles

Example 3-1-9: Prescription 9 Group component (mg)

Phenylethyl isothiocyanate 100

Carnauba wax 150

Paraffin wax 50

Lactose 100

Pregelatinized starch 40

Preparation process: firstly add carnauba wax and paraffin wax, then add phenethyl isothiocyanate, mix, add lactose and pre-gelatinized starch, stir evenly, sift through hot, sieve, whole, choose 14- 20 mesh granules, filled with capsules.

Example 3-1-10: Prescription 10

Preparation process: firstly, the carnauba wax is heated and melted, then phenethyl isothiocyanate is added, and after mixing, HPC is added, stirred uniformly, and then sieved by hot sifting, and 14-20 mesh particles are selected for the whole capsule, and the capsule is filled. Example 3-1-11 : Prescription 11

Preparation process: firstly, the carnauba wax is heated and melted, then phenethyl isothiocyanate is added, and after mixing, it is heated.

40 mesh sieve, whole grain selection 40-120 mesh particles. Weigh the prescribed amount of lactose and dibasic calcium hydrogen phosphate dihydrate, pass through a 50 mesh sieve 3 times, wet granulation with water as a binder, dry at 60 °C for 10 min, and select 40-120 mesh pellets. Take a prescribed amount of 5411-carnauba wax mixture and lactose-dihydrate dibasic calcium phosphate mixture and mix well, pre-compact. The small pieces are pulverized and passed through a 40 mesh sieve, and the pellets are directly compressed. The film diameter is 5mm, the tablet weight is 70mg, and it is packed into capsules, 4 small pieces each.

Example 3-1-12: Prescription 12

Pill core:

Coating liquid:

Ethyl cellulose 2g

Polyethylene glycol 0. 5g

Talc 5g

95% ethanol 100ml Preparation process: First, the hydrogenated castor oil is melted, and then phenethyl isothiocyanate is added, and after mixing, a diluent, a solubilizing agent and the like are added, mixed, and the pellet is prepared by a melt high-speed stirring method. The pellets were placed in a coating pan and sprayed into the coating solution to a weight gain of 5%, which was dried and filled.

Example 3-2: Sustained release test of sustained release preparation

Release test method: Chinese version of the Chinese Pharmacopoeia method, the basket method, 100 rpm, the dissolution medium is water, volume 500 ml, 37 °C.

The release profile of the sustained release granules prior to the formation of the final formulation form in a particular formulation is examined. The cumulative release of each formulation is as follows:

Example 3-3: Stability test of sustained release preparations

METHODS: The preparation samples were placed in open vials and placed in an oven at 60 °C. Samples were taken on days 0, 5 and 10, and the content and impurities were determined by reversed phase HPLC.

Result:

Analysis: The above data showed that the content of the main component isothiocyanate compound or its derivative in the prescription did not change significantly at 60 ° C for 10 days, indicating that the sustained release preparation provided by the present invention not only has a good sustained release effect. And there is an unexpected effect on stability. The stability of the preparation of the invention is mainly manifested in two aspects: 1) the preferred adjuvant of the invention has good compatibility with the isothiocyanate compound or its derivative; 2) the auxiliary material has a protective effect on the stability of the main drug . Example 4: Drug capsule experiment with different excipients

Example 4-1 : Preparation of capsules

Example 4-1-1 : Prescription 1

The phenethyl isothiocyanate and the dibasic calcium hydrogen phosphate dihydrate were ground uniformly, and talc powder was added and poured into a pullulan capsule twice through a 40 mesh sieve.

Example 4-1-2: Prescription 2

The phenethyl isothiocyanate and the dibasic calcium hydrogen phosphate dihydrate were ground uniformly, added with talc powder, and poured into a gelatin capsule twice through a 40 mesh sieve.

Example 4-1-3: Prescription 3

The phenethyl isothiocyanate was homogenized with calcium hydrogen phosphate dihydrate, added to the talc powder, and poured into a Vcaps® plant capsule twice through a 40 mesh screen.

Example 4-1-4: Prescription 4

The phenethyl isothiocyanate was homogenized with calcium hydrogen phosphate dihydrate, added to talc, and poured into Vcaps® Plus plant capsules twice through a 40 mesh screen. Example 4-1-5: Prescription 5

Take an appropriate amount of medium chain triglyceride, while stirring, add the prescribed amount of phenethyl isothiocyanate, vitamin E, and then add the remaining medium chain triglyceride, stir until uniform, fill gelatin Capsules are sealed and liquid hard capsules are obtained.

Example 4-1-6: Prescription 6

Preparation process: Take appropriate amount of soybean oil, and add the prescribed amount of phenethyl isothiocyanate and vitamin E in sequence while stirring, and then add the remaining soybean oil, stir until uniform, and use as a liquid medicine. After heating with glycerin and water to a suitable temperature, gelatin is added, stirred and dissolved, and kept for 1 hour, the foam is removed, filtered, added to a dropping machine, and the liquid paraffin is used as a condensate to collect the condensed soft capsule. Example 4-2: Stability test of capsules

Comparative preparation sample preparation:

Prescription 7 (prime)

The phenethyl isothiocyanate was mixed with calcium hydrogen phosphate twice through a 30 mesh sieve, and the lactose was added and sieved three times. Finally, talc powder was added, mixed, and compressed into 600 mg tablets.

Prescription 8 (Camerol Ou Bada coating, the main ingredient is polyvinyl alcohol (PVA))

The prescription 8 is coated, and the coating liquid is as follows:

The coating temperature was 30-35 ° C, the rotation speed was 22 rpm, the time was 30 min, and the coating weight gain was 4.2%.

Prescription 9 (METHOCEL (VLV Dow) coating material, the main ingredient is hydroxypropylmethylcellulose (HPMC)): Apply the prescription 7 and the coating solution is as follows: Ingredient amount ( g )

METHOCEL (VLV Dow) 33

Water 160

Total 193

The coating temperature was 25-30 ° C, the rotation speed was 22 rpm, the time was 23 min, and the coating weight gain was 2.3%.

The samples of the preparations in the prescriptions 1-9 were placed in a suitable container, placed at 60 ° C or 40 ° C, and a relative humidity of 75%, and samples were taken at different time points, and the content and impurities were determined by HPLC.

The results are shown in the following table:

Analysis: The above data showed that the content of the main component isothiocyanate compound or its derivative in the prescription was 60 ° C or 40 ° C, the relative humidity of 75%, the capsule did not change significantly, and the corresponding tablets There is a significant decrease in the coated tablets, indicating that the capsules provided by the present invention have an unexpected effect on stability, and can suppress the decrease in the content of the isothiocyanate compound or its derivative preparation during the standing process.

The advantages of the isothiocyanate compound capsule of the invention are mainly embodied in two aspects: 1) good stability and good performance of the preparation; 2) the capsule process is simple and easy to industrialize, compared to other dosage forms, And the drug loading is relatively high, which can meet the clinical needs. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entirety in the the the the the the the the the the In addition, it should be understood that various modifications and changes may be made to the present invention, and the equivalents of the scope of the invention.

Claims

Rights request

1. A preparation of isothiocyanate compounds or derivatives thereof, characterized in that the preparation is a sustained-release preparation, and the sustained-release preparation includes:

(a) A therapeutically effective amount of active ingredient, which is an isothiocyanate compound or a derivative thereof; Hekou

(b) Pharmaceutically acceptable carrier.

2. A preparation of isothiocyanate compounds or derivatives thereof, characterized in that the preparation is a capsule, and the capsule includes: a capsule shell, and a pharmaceutical composition placed inside the capsule shell ,

And the pharmaceutical composition includes:

(b) Pharmaceutically acceptable carrier.

3. The preparation according to claim 1 or 2, wherein the isothiocyanate compound is represented by formula (I), and its derivative is represented by formula (II):

A-NCS(I)

In formula I:

NCS is isothiocyanate group;

A is an XRi or a CR ₂ R ₃ R4, where

X is -(CH ₂ ) _n -, n is an integer from 0 to 6;

! ^ is methyl, tert-butyl, isopropyl, methylthio, methoxy, allyl, methallyl, cyclohexyl, methylsulfinyl, naphthyl, methylcyclohexyl, morpholine group, diethylamino group, benzoyl group, ethoxycarbonyl group, tert-octyl group, chlorine atom, trimethylsilyl group, substituted or unsubstituted phenyl group;

Among them, the "substitution" means that one or more H in the group is replaced by a substituent selected from the following group: halogen atom, methyl, bromomethyl, ethyl, methoxy, nitro, azide base, trifluoromethyl, difluoromethoxy, methylthio, cyano, trifluoromethoxy, trifluoromethylthio, tert-butoxycarbonyl, ethoxycarbonyl;

R ₂ , R ₃ , R ₄ are each independently H, phenyl or d. ₃ alkyl;

H S

■H C (II)

In equation II:

A is as defined in formula I;

H S

R ₅ is hydrogen or a group derived from the following compounds linked to the carbon atom of -NC- through a sulfur atom: N-acetyl cysteine, glutathione, cysteine (d. ₆ alkyl) ester , cysteinyl amino acid and cysteinyl amino acid (d. ₆ alkyl) ester.

4. The preparation according to claim 1, wherein the pharmaceutically acceptable carrier in the sustained-release preparation includes sustained-release materials and/or biodegradable polymer materials, and

The sustained and controlled release materials are selected from the following group: wax or grease materials, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, carbomer, sodium alginate, chitin, polyethylene, or combination thereof;

The biodegradable polymer material is selected from the following group: polysaccharides, proteins, polylactic acid, copolymer of lactic acid and glycolic acid, polylactic acid-polyethylene glycol copolymer, polylactide-polyethylene glycol Copolymer, polyhydroxyalkanoate, polyhydroxybutyrate, or combinations thereof.

5. The preparation according to claim 4, wherein the amount of the sustained and controlled release material accounts for 5-90wt% of the total weight of the preparation, preferably 10-70wt%; Hekou/or

The amount of the biodegradable polymer material accounts for 0-95wt% of the total weight of the preparation, preferably 10-85wt%.

6. The preparation according to claim 2, wherein the capsule shell is selected from the group consisting of: gelatin capsule shell, plant capsule shell, gastric capsule shell, enteric capsule shell, colon enteric capsule shell; The pharmaceutical composition placed inside the capsule shell is in a form selected from the following group: powder, granule, pellet, microsphere, small tablet, semi-solid, liquid, or a combination thereof.

7. The preparation according to any one of claims 1 to 6, characterized in that the preparation also includes one or more components selected from the following group: diluent, adsorbent, solubilizer, adhesive, Disintegrating agents, and optional lubricants.

8. The preparation according to claim 7, wherein when the preparation is a sustained-release preparation, the preparation has one or more characteristics selected from the following group:

(i) The diluent described in (i) is selected from the following group: glucose, fructose, lactose, maltose, trehalose, sorbitol, mannitol, maltitol, maltodextrin, sugar powder, dextrin, starch, pregelatinized starch, Microcrystalline cellulose, calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, magnesium carbonate, magnesium oxide, glyceryl palmitate stearate, or combinations thereof;

(ii) The adsorbent is selected from the following group: lactose, mannitol, dextrin, cyclodextrin, starch, pregelatinized starch, microcrystalline cellulose, powdered cellulose, calcium hydrogen phosphate, sodium chloride, Calcium sulfate, calcium carbonate, magnesium aluminum silicate, micronized silica gel, white clay, or combinations thereof;

(iii) The solubilizer described in (iii) is selected from the following group: povidone, crospovidone, polyethylene glycol, poloxamer, sodium lauryl sulfate, benzyl benzoate, cyclodextrin, egg Phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbates, fatty acid sorbitan, polyoxyethylene stearate, sucrose esters, or combinations thereof;

(iv) The binder is selected from the following group: povidone, gelatin, polyethylene glycol, polyoxyethylene, sucrose, chitosan, dextran, sodium alginate, maltodextrin, starch, fiber Vitamin derivatives, zeatin, or combinations thereof;

(V) The lubricant described in (V) is selected from the following group: stearic acid, magnesium stearate, zinc stearate, glyceryl palmitate stearate, glyceryl monostearate, micronized silica gel, talc, hydrogenated vegetable oil , polyethylene glycols, sodium lauryl sulfate, magnesium silicate, magnesium trisilicate, sodium hard fumarate, or combinations thereof;

Alternatively, when the formulation is a capsule, the formulation has one or more characteristics selected from the group consisting of:

(i) The diluent described in (i) is selected from the following group: glucose, maltose, maltitol, maltodextrin, lactose, fructose, powdered sugar, chitin, starch, pregelatinized starch, dextrin, mannitol, sorbitol, Calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, magnesium carbonate, magnesium oxide, microcrystalline cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyethylene, carbomer, hard Glyceryl palmitate, trehalose, sodium alginate, glyceryl behenate, glyceryl monostearate, polyethylene glycol monostearate, hydrogenated castor oil, hydrogenated vegetable oil, paraffin, beeswax, microcrystalline Wax, carnauba wax, Szechuan wax, white wax, albino wax, spermaceti wax, stearic acid, cetyl alcohol, cetyl alcohol ester wax, stearyl alcohol, cetyl alcohol, medium chain oil, soybean oil, olive oil , corn oil, or combinations thereof;

(ii) The adsorbent is selected from the following group: lactose, mannitol, starch, pregelatinized starch, dextrin, cyclodextrin, calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium carbonate, kaolin, silicon Magnesium aluminum phosphate, micronized silica gel, microcrystalline cellulose, powdered cellulose, or combinations thereof;

(iv) The binder is selected from the following group: starch, cellulose derivatives, povidone, gelatin, polyethylene glycol, sucrose, maltodextrin, sodium alginate, chitosan, dextran, Polyoxyethylene, zeatin, or combinations thereof;

(V) The disintegrant described in (V) is selected from the following group: starch, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, cross-linked polyvitamin Ketones, or combinations thereof; (Vi) The lubricant described in (Vi) is selected from the following group: magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycols, sodium lauryl sulfate, glyceryl palmitate stearate, monostearic acid Glycerides, magnesium silicate, magnesium trisilicate, sodium hard fumarate, stearic acid, zinc stearate, or combinations thereof.

9. The preparation according to claim 1, wherein the sustained-release preparation is selected from the following group: tablets, hard capsules, soft capsules, granules, dropping pills, pellets, microspheres, Microcapsules, polymer micelles, sustained-release small tablets, capsules, injections or implants.

10. The preparation of claim 2, wherein the capsule is selected from the group consisting of: hard capsules, soft capsules, immediate-release capsules, sustained- and controlled-release capsules, and enteric-coated capsules. , gastric-soluble capsules, colon-targeted capsules.

1 1. The preparation according to claim 7, characterized in that the preparation has one or more of the following characteristics: diluent and adsorbent account for 0-90wt% of the total weight of the preparation;

Solubilizer accounts for 0-50wt% of the total weight of the preparation;

The binder accounts for 0-50wt% of the total weight of the formulation;

Disintegrants account for 0-10wt% of the total weight of the preparation;

Lubricant accounts for 0-10wt% of the total weight of the formulation.

12. The preparation according to claim 1, wherein the pharmaceutically acceptable carrier in the sustained-release preparation contains one or more of the following components:

Sustained and controlled release materials, the sustained and controlled release materials account for 10-70wt% of the total weight of the preparation;

Biodegradable polymer material, the biodegradable polymer material accounts for 10-85wt% of the total weight of the preparation; diluent and adsorbent, the diluent and adsorbent account for 20-80wt% of the total weight of the preparation;

Solubilizer, the solubilizer accounts for 5-20wt% of the total weight of the preparation;

Binder, the binder accounts for 5-10wt% of the total weight of the preparation; and

Lubricant, the lubricant accounts for 0.1-5wt% of the total weight of the preparation.

13. The preparation of claim 2, wherein the pharmaceutically acceptable carrier in the capsule contains one or more of the following components:

Diluent and adsorbent, the diluent and adsorbent account for 20-80wt% of the total weight of the preparation;

Binder, the binder accounts for 5-10wt% of the total weight of the preparation;

Disintegrant, the disintegrant accounts for 0.1-5wt% of the total weight of the preparation; and

14. The preparation method of the preparation according to claim 1, characterized in that it includes the following steps:

Provide an active ingredient, which is an isothiocyanate compound or a derivative thereof;

Melt the sustained-release material and mix it with the active ingredient to form a first dispersion;

The first dispersion is mixed with other auxiliary materials and prepared into a formulation.

15. The use of the preparation according to any one of claims 1 to 14, characterized in that it is used to treat or prevent diseases selected from the following group: tumors, prostate diseases, skin diseases, hair loss, inflammation and other diseases.