CN1728983A - Process for the chemical stabilization of a solubilized retinoid in a solvent using a base - Google Patents
Process for the chemical stabilization of a solubilized retinoid in a solvent using a base Download PDFInfo
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- CN1728983A CN1728983A CNA2003801066839A CN200380106683A CN1728983A CN 1728983 A CN1728983 A CN 1728983A CN A2003801066839 A CNA2003801066839 A CN A2003801066839A CN 200380106683 A CN200380106683 A CN 200380106683A CN 1728983 A CN1728983 A CN 1728983A
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- chemical compound
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- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Toxicology (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Abstract
The invention relates to a process for the chemical stabilization of a solubilized retinoid within a pharmaceutical composition, and to an aqueous composition obtained by this process. The invention further relates to the use of the aqueous composition in cosmetics and dermatology.
Description
The present invention relates to make the chemically stable method of solubilization optic yellow kind compound in the medical composition, and relate to the waterborne compositions that obtains in this way by adding a kind of salifiable alkali of A1 vitamin group chemical compound that can make.
Known some A1 vitamin group chemical compound be not easy dissolved, and in the medical composition or the compositions of making up, lack chemical stability (Szuts " solubility of retinoids inwater ", Arch.Biochem.Biophys.1991,287:297-304).The a kind of of this problem may solution be to mix this effective ingredient so that its solubilising with discrete form.Yet dispersive effective ingredient is compared with the effective ingredient of solubilising, is not easy to discharge from local prescription.Therefore, in order to increase the release of this effective ingredient, verified advantageously the effort prepared this effective ingredient with solubilized forms.
And then a kind of finished product especially under the situation of medical composition or cosmetic composition, must be saved physical chemistry benchmark accurately from damage at its whole life period, makes to guarantee its medical quality or cosmetic quality.In the middle of these benchmark, rheologic behavio(u)r must be saved from damage.They have defined behavior and quality when said composition is used, and the release performance of this main constituent.
Specifically, this A1 vitamin group chemical compound helps for example acne treatment of Local treatment as the prescription of gel or oil-in-water emulsion, especially because it has avoided staying greasy sensation on skin.Prescription as Water in Oil emulsion may be preferably for psoriasis treatment.
Now, according to A1 vitamin group chemical compound of the present invention, in the oil-based solvent medium and with the aqueous solvent of the prescription compatibility of the topical composition of gel-type or emulsion type in, be not easy to dissolve and deficient in stability.
In the patent application WO 85/02767 that is entitled as " containing in water medical composition of unstable or poor molten medicine and preparation method thereof ", Janssen Pharmaceutica company points out, " if this molecule has acidic groups or basic group; then might improve its dissolubility in water by generating a kind of salt, but this causes that drug effect reduces or chemical stability reduces ".Therefore, according to this prior art, do not encourage those skilled in the art to make its effective ingredient salify, in the hope of giving them with chemical stability.
Now, surprisingly, applicant has developed a kind of solubilization optic yellow kind compound chemical stabilizing method that can make its salifiable alkali that adds, and it is solvable and chemically stable in gel-type or emulsion type water-base compositions that described A1 vitamin group chemical compound becomes.Use the compositions that obtains according to method of the present invention to comprise at least a so and solubilization optic yellow kind compound with good chemical stability, promptly it does not demonstrate this effective ingredient and passes in time and degrade 4～40 ℃ temperature; Said composition further has good physical stability, and promptly it does not demonstrate 4～40 ℃ of temperature-viscosity and passes in time and descend, and does not demonstrate and at high temperature pass in time and be separated or ooze out.
Surprisingly, thus applicant have been found that and a kind ofly make its salt in situ coating in waterborne compositions that the method for the excellent chemically stable effect of this solubilization optic yellow kind compound is provided by adding a kind of alkali.
Therefore, the present invention relates to a kind of chemical stabilizing method of solubilization optic yellow kind compound in waterborne compositions by a kind of alkali of interpolation.The invention further relates to the waterborne compositions that obtains with the inventive method, be included in and accept in the medium at least a A1 vitamin group chemical compound on a kind of physiology and at least aly can make the salifiable alkali of this effective ingredient, make to make its solubilising and give it with chemical stability.
Advantageously, comprising one according to waterborne compositions of the present invention contains A1 vitamin group chemical compound, cosolvent and can make the mutually effective of the salifiable alkali of this A1 vitamin group chemical compound, a water and the oil phase that under the situation of emulsion, also can contain emulsifying agent and additive that contains the emulsifying agent under water and randomly another kind of solvent, gelating agent and the emulsion situation." according to waterborne compositions of the present invention " is appreciated that to meaning a kind of compositions that surpasses 50% high percent water that contains ideally.
According to compositions of the present invention, this contains at least a A1 vitamin group chemical compound, a kind of A1 vitamin group chemical compound precursor or a kind of A1 vitamin group compound derivatives effectively mutually more precisely.
" A1 vitamin group chemical compound " (retinoid) be appreciated that for mean any contain can with alkali give birth to salifiable group, can with RAR and/or the bonded chemical compound of rxr receptor." A1 vitamin group chemical compound precursor " be appreciated that for mean its biology moment precursor or substrate with and precursor." A1 vitamin group compound derivatives " be appreciated that for mean its metabolism biological and chemical derivative thereof both.
This A1 vitamin group chemical compound better is a kind of propargyl alcohol derivative, is one of a kind of racemic compound of following formula or enantiomer particularly well:
Be 2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-and the 1-propinyl] benzoic acid, S-(+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-the 1-propinyl] benzoic acid or R-(-)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-the 1-propinyl] benzoic acid.
For the present invention's purpose, can use single enantiomer or its mixture in these chemical compounds, comprise racemic mixture.
Certainly, the quantity according to A1 vitamin group chemical compound in the compositions of the present invention will more specifically depend on the related A1 vitamin group chemical compound and the quality of desirable treatment.
Gross weight with said composition is a benchmark, and the A1 vitamin group compound concentration is between 0.0001～20wt% preferably.
Also contain the cosolvent that ethylene glycol type cosolvent or other and this aqueous medium have affinity according to effective phase of compositions of the present invention.These hydrophilic solvents that serve as cosolvent also make the quantity that can reduce alkali, thus with the pH of no diol combination thing specific energy reduction pH mutually.Therefore, resulting pH more approaches the pH of skin.And then known glycol can improve the penetration of effective ingredient.
The limiting examples of the cosolvent that can mention is PEG-6 three (caprylic/capric) glyceride (Softigen 767), Nonyl pheno (10) ether (Renex 690), anhydrous sorbitol polyoxyethylene (20) ether stearate (Tween 60), anhydrous sorbitol polyoxyethylene (20) ether stearate (Polysorbate 60), Cremophore RH 60, the PEG-35 Oleum Ricini, Arlasolve, Isosorbide dimethyl ether, Labeasol, PEG-8 three (caprylic/capric) glyceride, phenoxyethanol, or glycol propylene glycol for example, two polypropylene glycols, butanediol, PEG400 (PEO-400) and ethyl diethylene glycol ether.According to better cosolvent of the present invention is propylene glycol and two polypropylene glycols.
The concentration of cosolvent is 5～50%, better 10～20% in according to compositions of the present invention.
At least aly can make the salifiable alkali of this A1 vitamin group chemical compound according to containing effectively mutually of compositions of the present invention.
The non-limiting example of the alkali that can mention is for example sodium hydroxide (NaOH) or a Lithium hydrate (LiOH) of inorganic base, and organic base is N-methyl D-glycosamine or trometamol, ammonia (NH for example
4OH), basic amino acid for example D-glycosamine or N-methylglucosamine of L-lysine, L-arginine, L-ornithine or glycine or various alkali for example.
Better alkali according to compositions of the present invention is sodium hydroxide or L-lysine.
With this A1 vitamin group chemical compound is benchmark, and this alkali better uses with the concentration in 0.5～10 molar equivalent scope.
This A1 vitamin group chemical compound is a solubilising and salifiable in the presence of this alkali, promptly
A) this cosolvent and this alkali form effectively mutually in, simply by magnetic agitation,
B) aqueous phase of forming at this solvent, cosolvent and alkali, this water also can contain those described in the additive text for example of the present invention.
Water according to compositions of the present invention contains for example water of a kind of solvent, a kind of flower perfume such as Centaurea cyanus water, or a kind of natural hot water or mineral water, be selected from water such as Vittel, Vichy source water, Uriage water, Roche Posay water, Bourboule water, Enghien-les-Bains water, Saint Gervais-les-Bains water, N é ris-les-Bains water, Allevard-les-Bains water, Digne water, Maizieres water, Neyeac-les-Bains water, Lons-le-Saunier water, Bonnes water, Rochefort water, Saint Christau water, Fumades water, Tercis-les-Bains water, Avene water and Aix-les-Bains water, a kind of alcohol such as ethanol, or another kind of hydrophilic solvent.
Solvent is a water preferably, be with better more than 50%, especially the concentration more than 75% exists with gel form.
According to compositions of the present invention better is that form with hydrogel exists.
" hydrogel " is appreciated that to meaning a kind of compositions that contains a kind of viscoelastic body that forms from colloidal suspension (gelating agent) at aqueous phase.
NOv é on) or Sepigel 305 types (supplier: acrylate derivative SEPPIC) non-limiting example of the gelating agent that can mention is Carbopol type (supplier:, Natrosol type (supplier: Aqualon) or Methocel type (supplier: cellulose derivative DowChemical), Keltrol type (supplier: Xanthan gum KELCO), or its mixture.
Gelating agent is that for example Carbopol 980 is deutero-from acrylate derivative family preferably.
Aforesaid gelating agent can be with in better 0.05～15% scope, especially the concentration in 0.1～5% scope be used.
According to another kind of compositions of the present invention is a kind of emulsion, thereby comprises a kind of emulsifying agent in this water and an oil phase.
The non-limiting example of the emulsifying agent that can the mention glycerol that to be ICI company sell with Simusol 165 titles with Arlacel 165 titles or SEPPIC company (with) the PEG-100 stearate, the polyethoxylated fatty acid ester is the Arlatone 983 of ICI company for example, relevant with ICI company with polyethoxylated (21) stearyl alcohol of Beij 721 titles sale, polyethoxylated (2) stearyl alcohol with the sale of Brij 72 titles, the sorbitan ester sorbitan monooleate that for example ICI company sells with Arlacel 80 titles or Croda company sells with Crill 4 titles, anhydrous sorbitol half oleate that ICI company sells with Montane 83 titles with sale of Arlacel 83 titles or SEPPIC company, or anhydrous sorbitol isostearate, high HLB is arranged is HLB more than or equal to 7 fatty alcohol ether, 16/octodecyl alcohol polyoxyethylene (12) ether (Ceteareth-12) of selling with Eumulgin B1 title of 16/octodecyl alcohol polyoxyethylene (20) ether (Ceteareth-20) sold with Eumulgin B2 title of Cognis company or Cognis company for example, or low HLB is arranged is that HLB is lower than 7 fatty alcohol ether, for example stearyl polyoxyethylene (2) ether Steareth-2 for example.
According to better emulsifying agent of the present invention is 16/octodecyl alcohol polyoxyethylene (20) ether (Ceteareth-20).
According to compositions of the present invention, be benchmark with the gross weight of said composition, favourable comprising can reach the suitable emulsifying systems of 15wt%, better 0.05～8wt%, 0.1～2wt% especially.
The example of the oil-phase component that can mention is oils, especially mineral oil (liquid paraffin), plant source oils (American Avocado Tree oil, soybean oil), animal sources oils (lanolin oil), synthetic oils (perhydro Squalene), silicone oil (annular dimethyl polysiloxane) and fluorinated oil (PFPE).Operable other fatty material is for example kitol, fatty acid, wax and glue, especially a silicone gum of aliphatic alcohol.
Be preferably the use liquid paraffin.
Also can comprise normally used any additives in cosmetics or the field of medicaments according to compositions of the present invention, for example cyclodextrin, co-emulsifier, chelating agen, antioxidant, sunscreen, antiseptic, filler, electrolyte, wetting agent, coloring agent, usual mineral or organic base or acid, flavouring agent, quintessence oil, cosmetic effective ingredient, hydrating agents, vitamin, essential fatty acid, sphingolipid, artificial tanned chemical compound DHA, skin lubrication and protective agent allantoin for example for example.Certainly, those skilled in the art will carefully select this or these optional auxiliary compounds and/or its quantity, make unaffected or unaffected in fact according to the advantageous property of compositions of the present invention.
Gross weight with said composition is a benchmark, and these additives can be present in the said composition with the quantity of 0～20wt%.
The example of the cyclodextrin that can mention is beta-schardinger dextrin-or HP-.
The example of the chelating agen that can mention is ethylenediaminetetraacetic acid (EDTA) and derivant or salt, dihydroxyethylglycin, citric acid, tartaric acid or its mixture.
The example of the anti-stimulant that can mention is Aloe, allantoin, oatmeal or tocopherol acetas.
The example of the antiseptic that can mention is alkyl benzyl dimethyl ammonium chloride, phenyl phenol, benzylalcohol, N-(methylol)-N-(1, the two methylols-2 of 3-, 5-dioxy-4-imidazolidinyl)-N '-(methylol) urea, p-Hydroxybenzoate or its mixture.
The examples of humectants that can mention is glycerol and Sorbitol.
Better pH value according to compositions of the present invention is the pH that approaches skin pH, promptly between 5～7, more fortunately between 5.5～6.
Therefore, the present invention relates to make the chemically stable method of solubilization optic yellow kind compound in the medical composition by adding a kind of salifiable alkali of A1 vitamin group chemical compound that can make.
Specifically, the present invention relates to make the chemically stable method of following formula solubilization optic yellow kind compound in the medical composition by adding a kind of salifiable alkali of A1 vitamin group chemical compound that can make:
The invention further relates to the medicine or the cosmetics waterborne compositions that obtain with method of the present invention.
Specifically, the present invention relates to obtain with the inventive method, be used for the medicine or the cosmetics waterborne compositions of skin, skin adventitia or mucosa local application with form of hydrogels, it is characterized in that it a kind of with the local application compatibility of skin, skin adventitia or mucosa physiological accepted to contain in the medium following ingredients:
A) 0.01～5% following formula A1 vitamin group chemical compound:
B) 1～10 molar equivalent is a kind of can make the salifiable inorganic base of this A1 vitamin group chemical compound;
C) 0.01～5% a kind of acrylate derivative as gelating agent;
D) 40～80% water as main solvent; With
E) 5～20% 1 kinds of glycol as cosolvent.
According to a kind of better waterborne compositions of the present invention, it is characterized in that it comprises:
A) 0.1%S-(+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-1-propinyl] benzoic acid;
B) 2 molar equivalents are used to make the salifiable sodium hydroxide of this A1 vitamin group chemical compound;
c)0.5％Carbopol 980；
D) 65～75% water; With
E) 15% propylene glycol.
The invention further relates to compositions as mentioned above as medicine.
The invention further relates to the purposes of new compositions on cosmetics and dermatological as mentioned above.
When especially being intended to be used for the dermatological purposes according to compositions of the present invention, a release and the permeability parameters that important parameter is an effective ingredient, to this, applicant has also proposed by means of being improved according to prescription of the present invention.
Surprisingly, applicant has been found that above-described better prescription just provides extraordinary result with regard to the release of skin and infiltration, this proof even be better than containing the result that simple gel provided of permeability glycol at high proportion.Therefore, the compositions according to the present invention obtains except that the good chemical stability of this A1 vitamin group chemical compound, also has good effective ingredient release/osmosis.
Because the A1 vitamin group chemical compound is in the remarkable activity of cell differentiation and proliferation field, the present composition especially is suitable for following treatment field:
1) the dermatosis main suit who is used to cure the disease and interrelates with the keratinization imbalance that relates to differentiation and propagation, be particularly useful for treating acne vulgaris, blackhead, polymorphic acne, acne erythematosa, nodulocystic acne, block acne, senile acne, for example Exposure to Sunlight acne of Secondary cases acne, drug induced acne or keloid acne, and hidradenitis suppurativa;
2) keratinization that is used for the treatment of other type is lacked of proper care, especially ichthyosis (xeroderma), ichthyosis sample state, follicular keratosis, keratosis palmaris, leukoplakia and leukoplakia sample state and skin or mucosa (cheek) lichen;
3) other dermatosis main suit who is used to cure the disease and interrelates with the keratinization imbalance that inflammatory component and/or immune allergia composition are arranged, especially the psoriasis of form of ownership, no matter skin, mucosa also be meant (toe) first even psoriasic rheumatism, or atopic dermatitis eczema or breathe atopy or gum hypertrophy for example; These chemical compounds can be used for some the inflammatory main suit who does not show the keratinization imbalance, for example folliculitis;
4) be used for the treatment of propagation all skins or epidermis, no matter benign or virulent, also no matter whether be viral source, for example verruca vulgaris, verruca plana, molluscum contagiosum and epidermodysplasia verruciformis, and the papillomatosis oral cavity or scarlet and the hypertrophy that can bring out by ultraviolet, especially under the situation of actinic keratosis;
5) be used for repairing or preventing and treating skin aging, no matter photo-induced or chronic, or be used to reduce pigmentation, perhaps with the chronic aging or photochemical aging any pathology symptom that interrelates;
6) be used for the treatment of prevention or cure the healing imbalance or the skin ulcer of ability aspect, be used to prevent or repair the atrophic striped, or be used for promoting to cure;
7) be used to prevent and treat the sebaceous gland imbalance, for example high seborrheic dermatitis of acne sample or simple seborrheic dermatitis;
8) be used for the treatment of any fungal source skin main suit, for example tinea pedis and tinea versicolor;
9) be used for the treatment of the dermatological main suit that immunizing composition is arranged;
10) be used for the treatment of the cutaneous disorder that is exposed to ultraviolet radiation and causes; With
11) be used for the treatment of the dermatological main suit that inflammation or infection with the hair follicle surrounding tissue interrelate, especially those that cause owing to thin biological cluster or infection, particularly impetigo, seborrheic dermatitis, folliculitis or Sycosis vulgaris, perhaps those relate to any bacteriocin or epiphyte pharmaceutical person.
Be specially adapted to acne vulgaris or psoriasic preventative or therapeutic treatment according to compositions of the present invention.
Also be applicable to cosmetic field according to compositions of the present invention, be particularly useful for treating easy generation acne skin, be used to cause that hair regeneration is long or anti-loss, be used to prevent and treat skin or hair oil outward appearance, be used to provide protection, be used for the treatment of the physiological xerosis cutis or be used to prevent and/or prevent and treat photo-induced or chronic aging sun adverse effect.
Also be applicable to health and hair health according to compositions of the present invention.
The present invention also relates to alkali and be used for comprising the medical composition solubilization optic yellow kind compound of at least a A1 vitamin group chemical compound, main solvent and cosolvent by salifiable chemically stable purposes.
The example of the prescription that below provides provides the explanation to the compositions that obtains according to the inventive method with this method, but does not limit its scope.Relate to the result of physical stability and chemical stability and relate to the release of effective ingredient and the result of infiltration also is that mode with explanation provides.
Embodiment 1: according to the chemically stable side of solubilization optic yellow kind compound in the medical composition of the present invention
Method
This A1 vitamin group chemical compound solubilising and salify in the presence of this alkali, promptly
A) this cosolvent and alkali form effectively mutually in, pass through magnetic agitation simply;
B) aqueous phase of forming at this solvent, cosolvent and alkali, this water also can contain additive, those described in the text for example of the present invention.
Following examples relate to described method and prepare its compositions mutually effective and/or water.
Embodiment 2: hydrogel
| Trade name | The INCI title | ％ |
| Water methyl parahydroxybenzoate glycerol allantoin EDTA 2 Na CARBOPOL 980 NF | Water methyl parahydroxybenzoate glycerol allantoin ethylenediamine-tetraacetic acid sodium Carbomer | 75.88 0.15 5.00 0.20 0.10 0.50 |
| Sodium hydroxide (10% solution) | Sodium hydroxide | 2.00 |
| Propylene glycol S-(+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-the 1-propinyl] benzoic acid sodium hydroxide (1% solution) | Propylene glycol effective ingredient sodium hydroxide | 15.00 0.10 1.07 |
Program:
-effective phase: this is use embodiment 1a) the magnetic force solubilising of method by propylene glycol, sodium hydroxide and A1 vitamin group chemical compound prepare.
-water: under the effect of heat (80 ℃), guarantee the complete solubilising of methyl parahydroxybenzoate, glycerol, allantoin and EDTA.
Then, guarantee that Carbopol is in this dispersion fully in mutually.This gel that neutralizes, and will incorporate into wherein effectively mutually.
Embodiment 3: the hydrogel that cyclodextrin is arranged
| Trade name | The INCI title | ％ |
| Water methyl parahydroxybenzoate glycerol CARBOPOL 980 NF | Water methyl parahydroxybenzoate glycerol Carbomer | 40.43 0.15 5.00 0.50 |
| Sodium hydroxide (10% solution) | Sodium hydroxide | 2.00 |
| Water propylene glycol beta-schardinger dextrin-sodium hydroxide (1% solution) S-(+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-the 1-propinyl] benzoic acid | Water propylene glycol cyclodextrin sodium hydroxide effective ingredient | 45.00 5.00 0.75 1.07 0.10 |
Program:
Effective phase-also be in this case water-be use embodiment 1b) method prepares by the solubilising of this A1 vitamin group chemical compound in the presence of sodium hydrate aqueous solution, propylene glycol and cyclodextrin.
Embodiment 4: oil-in-water emulsion
| Trade name | The INCI title | ％ |
| MARCOL 172 EUMULGIN B2 BHT propyl p-hydroxybenzoate | Mineral oil Ceteareth-20 butylated hydroxytoluene propyl p-hydroxybenzoate | 10.00 0.50 0.05 0.15 |
| Water glycerol allantoin CARBOPOL 980 NF PEMULEN TR1 | Water glycerol allantoin Carbomer acrylates/acrylic acid C10-30 alkane ester cross-linked copolymers | 65.78 5.00 0.20 0.15 0.30 |
| Sodium hydroxide (10% solution) | Sodium hydroxide | 1.70 |
| Propylene glycol S-(+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-the 1-propinyl] benzoic acid | The propylene glycol effective ingredient | 15.00 0.10 |
| Sodium hydroxide (1% solution) | Sodium hydroxide | 1.07 |
Program:
-effective phase: this is use embodiment 1a) the magnetic force solubilising of method by propylene glycol, sodium hydroxide and A1 vitamin group chemical compound prepare.
-water: water, glycerol and allantoin weighed and put into the prescription beaker, be warming up to 80 ℃.
Stir with Rayneri, guarantee the dissolving fully of Carbopol and Pemulen.
-oil phase: weighing comprises the oil phase of Marcol 172, Eumulgin B2, BHT and propyl p-hydroxybenzoate, and is warming up to 80 ℃.
Be stirred in 80 ℃ with Rayneri and carry out emulsifying in 20 minutes, be cooled to 50 ℃ then gradually.
At 50 ℃, this gelating agent and this effective phase of interpolation under agitation neutralize.
Embodiment 5: oil-in-water emulsifiers
| Trade name | The INCI title | ％ |
| MARCOL 172 EUMULGIN B2 BHT | Mineral oil Ceteareth-20 butylated hydroxytoluene | 10.00 0.50 0.05 |
| Water glycerol CARBOPOL 980 NF phenyl phenol PEMULEN TR1 | Water glycerol Carbomer phenyl phenol acrylates/acrylic acid C10-30 alkane ester cross-linked copolymers | To 100 an amount of 5.00 0.2 1.00 0.30 |
| Sodium hydroxide (10% solution) | Sodium hydroxide | 1.80 |
| Two polypropylene glycol S-(+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-the 1-propinyl] benzoic acid sodium hydroxide (1% solution) | Two polypropylene glycol effective ingredient sodium hydroxide | 15.00 0.10 1.07 |
Program:
-effective phase: this is use embodiment 1a) the magnetic force solubilising of method by two polypropylene glycols, sodium hydroxide and A1 vitamin group chemical compound prepare.
-water: with water, glycerol and phenoxyethanol be weighed to the prescription beaker in and be warming up to 80 ℃.
Stir the complete solubilising of guaranteeing Carbopol and Pemulen with Rayneri.
-oil phase: weighing comprises the oil phase of Marcol 172, Eumulgin B2, BHT, and is warming up to 80 ℃.
Be stirred in 80 ℃ with Rayneri and carry out emulsifying in 20 minutes, then, be cooled to 50 ℃ gradually.
At 50 ℃, this gelating agent and add effective phase while stirring neutralizes.
Embodiment 6: hydrogel
| Trade name | The INCI title | ％ |
| Water methyl parahydroxybenzoate BHT glycerol allantoin CARBOPOL 980 NF | Water methyl parahydroxybenzoate butylated hydroxytoluene glycerol allantoin Carbomer | 75.93 0.15 0.05 5.00 0.20 0.50 |
| Sodium hydroxide (10% solution) | Sodium hydroxide | 2.00 |
| Propylene glycol S-(+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-the 1-propinyl] benzoic acid sodium hydroxide (1% solution) | Propylene glycol effective ingredient sodium hydroxide | 15.00 0.10 1.07 |
Program:
-effective phase: this is use embodiment 1a) magnetic force solubilising by propylene glycol, sodium hydroxide and A1 vitamin group chemical compound prepares.
-water: under the effect of heat (80 ℃), guarantee the dissolving fully of methyl parahydroxybenzoate, allantoin and BHT.Guarantee the dispersion fully of Carbopol during this mutually then.This gel that neutralizes, and this is incorporated into wherein effectively mutually.
Embodiment 7: hydrogel
| Trade name | The INCI title | ％ |
| Water methyl parahydroxybenzoate BHT glycerol allantoin CARBOPOL 980 NF | Water methyl parahydroxybenzoate butylated hydroxytoluene glycerol allantoin Carbomer | 75.93 0.15 0.05 5.00 0.20 0.50 |
| Sodium hydroxide (10% solution) | Sodium hydroxide | 2.00 |
| Two polypropylene glycol S-(+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-the 1-propinyl] benzoic acid sodium hydroxide (1% solution) | Two polypropylene glycol effective ingredient sodium hydroxide | 15.00 0.10 1.07 |
Program:
-effective phase: this is use embodiment 1a) the magnetic force solubilising of method by two polypropylene glycols, sodium hydroxide and A1 vitamin group chemical compound prepare.
-water: under the effect of heat (80 ℃), guarantee the dissolving fully of methyl parahydroxybenzoate, glycerol, allantoin and BHT.
Then, guarantee that Carbopol is in this dispersion fully in mutually.Make the neutralization of this gel and this is incorporated into wherein effectively mutually.
Embodiment 8: hydrogel
| Trade name | The INCI title | ％ |
| Water methyl parahydroxybenzoate BHT glycerol Aloe CARBOPOL 980 NF | Water methyl parahydroxybenzoate butylated hydroxytoluene glycerol Aloe Carbomer | 75.93 0.15 0.05 5.00 0.20 0.50 |
| Sodium hydroxide (10% solution) | Sodium hydroxide | 2.00 |
| Two polypropylene glycol 2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-the 1-propinyl] benzoic acid sodium hydroxide (1% solution) | Two polypropylene glycol effective ingredient sodium hydroxide | 15.00 0.10 1.07 |
Program:
-effective phase: this is use embodiment 1a) the magnetic force solubilising of method by two polypropylene glycols, sodium hydroxide and A1 vitamin group chemical compound prepare.
-water: under the effect of heat (80 ℃), guarantee the dissolving fully of methyl parahydroxybenzoate, glycerol, Aloe, BHT and water.
Then, guarantee that Carbopol is in this dispersion fully in mutually.This gel and this is incorporated into wherein effectively mutually neutralizes.
Embodiment 9: stability
(9.A.S-+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl
Naphthalene-2-yl)-and the 1-propinyl] benzoic acid (hereinafter to be referred as the effective ingredient in the present embodiment) is in letter
Salify and not salifiable chemical stability in single two alcogel
In order to verify this effective ingredient salify or the chemical stability during salify not, 5 simple in composition have been prepared.
The composition details of these prescriptions:
| Component (%) | Prescription No.1 | Prescription No.2 | Prescription No.3 | Prescription No.4 | Prescription No.5 |
| Effective ingredient | 0.1 be into salt form | 0.1 be by the salifiable form of alkali of adding | 0.1 be by the salifiable form of alkali of adding | 0.1 be by the salifiable form of alkali of adding | 0.1 be by the salifiable form of alkali of adding |
| Propylene glycol | 75 | 75 | 75 | 75 | 75 |
| Ethanol | 5 | 5 | 5 | 5 | 5 |
| Water | 20 | 18 | 18 | 18 | 18 |
| L-lysine | 1.02 equivalent | ||||
| Lithium hydrate | 1.02 equivalent | ||||
| Sodium hydroxide | 1.02 equivalent | ||||
| Triethanolamine | 1.02 equivalent |
Effective ingredient concentration is 0,15 and 28 day timing, the results are shown in the following table:
| Prescription | Theoretical concentration (%m/m) | 0 o'clock concentration (%) | 15 days concentration (%) | 28 days concentration (%) |
| Prescription 1 | 99 | 98 | 64 | 47 |
| Prescription 2 | 103 | 98 | 95 | 97 |
| Prescription 3 | 99 | 99 | 98 | 99 |
| Prescription 4 | 99 | 100 | 96 | 98 |
| Prescription 5 | 99 | 100 | 96 | 99 |
These results demonstrate chemical stability excellence under the situation that this effective ingredient exists with the one-tenth salt form.
9.B. embodiment 2: the physics of hydrogel and chemical stability
| Room temperature and the 45 ℃ physical stability after 1 month | NNC 1 |
| Room temperature and the 45 ℃ physical stability after 2 months | NNC |
| The chemical stability of TO | 99.4％ |
| 45 ℃ of the chemical stability of room temperature after 1 month | 97.7％ 97.6％ |
| 45 ℃ of the chemical stability of room temperature after 3 months | 99.4％ 97.6％ |
9.C. embodiment 3: the physics of cyclodextrin gel and chemical stability
| Room temperature and the 45 ℃ physical stability after 1 month | NNC |
| Room temperature and the 45 ℃ physical stability after 2 months | NNC |
| The chemical stability of TO | 100.1％ |
| 45 ℃ of the chemical stability of room temperature after 1 month | 100.0％ 99.6％ |
| 45 ℃ of the chemical stability of room temperature after 3 months | 102.2％ 101.7％ |
9.D. embodiment 5: the physical and chemical stability of oil-in-water emulsion
| Room temperature and the 45 ℃ physical stability after 1 month | NNC |
| Room temperature and the 45 ℃ physical stability after 2 months | NNC |
| The chemical stability of TO | 100.7％ |
| 45 ℃ of the chemical stability of room temperature after 1 month | 98.8％ 98.4％ |
| 45 ℃ of the chemical stability of room temperature after 2 months | 100.7％ 99.5％ |
| 45 ℃ of the chemical stability of room temperature after 3 months | 98.7％ 97.6％ |
The above all has the excellent physical and the chemical stability of solubilising effective ingredient according to all compositionss of the present invention.
1NNC=does not have significant change.
Embodiment 8: the result relevant with the release/infiltration of effective ingredient
Embodiment 6 and 2 kinds of gels of 7 by be rich in relatively testing of the simple two alcogel permeability glycol, that following prescription is arranged, in the hope of release and the level of interpenetration of assessment according to effective ingredient in the better prescription of the present invention.
Experimental program:
Stripped release/infiltration according to effective ingredient in the compositions of the present invention can be assessed with whole fell.Test recipe is to glass diffusion cell (3ml; 1cm
2) act on 16 hours.Use the whole skin of no skin tumour.This skin is fixed on the diffusion cell, corium is contacted with the physiological salt solution (accepting liquid) of having added the 0.25wt% emulsifying agent.This system keeps (this is accepted liquid and does not pass in time and upgrade) with static mode.
Use comes from make up operating abdominal part and/or breast flap.This prescription is with 10mg prescription/cm
2Rate action in these 3 kinds of different dermatological specimens.These are used no occlusion ground and carry out.Use when repeating when these, these prescriptions are used 6 times altogether.
When these are used when finishing, all to remove the surface excessive for each diffusion cell, and butt joint liquid body and skin sampling.Epidermis (comprising horny layer) is separated from corium.Each test recipe is all calculated the overall balance of effective ingredient, consider excessive part and in skin and the quantity of accepting to survey in the liquid.The concentration of effective ingredient is (to quantize the limit: 1ng.ml with there being APCI/MS/MS to detect
-1) HPLC measure.
Simple two alcogel:
| Trade name | The INCI title | ％ |
| The pure rectification ethanol of propylene glycol Purified Water L-lysine (50% solution) 2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl-2-naphthyl)-the 1-propinyl] benzoic acid KLUCEL HF | Propylene glycol alcohol water lysine effective ingredient hydroxypropyl cellulose | 75.00 5.00 18.822 0.078 0.1 1 |
Release/infiltration result:
| Prescription | The effective ingredient quantity of accepting to survey in the medium |
| Simple two alcogel | 0.35 ± 0.06 μ g (3.6% application dosage) |
| Gel according to embodiment 7 | 0.69 ± 0.25 μ g (8.0% application dosage) |
| Gel according to embodiment 6 | 1.05 ± 0.13 μ g (11.4% application dosage) |
These results show, except that the chemically stable of this effective ingredient, have improved the bioavaliability of effective ingredient in the skin (with reference gel phase ratio, being respectively 2～3 times) according to optimization of C of the present invention.
Claims (14)
1. the chemical stabilizing method of solubilization optic yellow kind compound in a kind of medical composition that comprises at least a A1 vitamin group chemical compound, a kind of main solvent and a kind of cosolvent is characterized in that a kind of alkali adds for making this A1 vitamin group chemical compound salify.
2. according to the method for claim 1, it is characterized in that this A1 vitamin group chemical compound has formula (Ia):
3. with the method waterborne compositions that obtain, that be used for topical use of claim 1 or 2, comprise following ingredients at least:
A) from the deutero-A1 vitamin group chemical compound of propargyl alcohol;
B) be used to make the salifiable alkali of this A1 vitamin group chemical compound
C) main solvent; With
D) cosolvent.
4. according to the waterborne compositions of claim 3, it is characterized in that this A1 vitamin group chemical compound has formula (Ia):
5. according to the compositions of claim 3 or 4, it is characterized in that being used to make the salifiable alkali of this A1 vitamin group chemical compound to be selected from inorganic base, organic base and basic amino acid.
6. according to the compositions of claim 5, it is characterized in that being used to make the salifiable alkali of this A1 vitamin group chemical compound is sodium hydroxide.
7. according to the compositions of claim 6, it is characterized in that, is benchmark with this effective ingredient, and this alkali is that the concentration with 1～10 molar equivalent exists.
According in the claim 3～7 any one, be the waterborne compositions of local application gel form, it is characterized in that it comprises:
A) the A1 vitamin group chemical compound of 0.01～5wt% following formula:
B) 1～10 molar equivalent is used to make the salifiable inorganic base of this A1 vitamin group chemical compound;
C) 0.01～5wt% acrylate derivative as gelating agent;
D) 40～80wt% is as the water of main solvent; With
E) 5～20wt% is as the glycol of cosolvent.
9. according to the waterborne compositions of claim 8, it is characterized in that it comprises:
A) 0.1% S-(+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-1-propinyl] benzoic acid;
B) 2 molar equivalents are used to make the salifiable sodium hydroxide of this A1 vitamin group chemical compound;
c)0.5％ Carbopol 980；
D) 65～75% water; With
E) 15% propylene glycol.
10. according to any one compositions in the claim 3～9, as a kind of medicine.
11. the purposes according to the compositions of any one in the claim 3～10 is used to make a kind of pharmaceutical preparation, the dermatological main suit that this pharmaceutical preparation can be used for preventing or treatment and cell differentiation and/or propagation imbalance and/or keratinization imbalance interrelate.
12. the purposes according to the compositions of any one in the claim 3～11 is used to make a kind of pharmaceutical preparation, this pharmaceutical preparation is used for prevention or treatment acne or psoriasis.
13. cosmetic use according to the compositions of any one in the claim 3～12, be used for the treatment of easy generation acne skin, be used to cause that hair regeneration is long or anti-loss, be used to prevent and treat skin or hair oil outward appearance, be used to provide protection, be used for the treatment of the physiological dry skin or be used to prevent and/or prevent and treat photo-induced or chronic aging sun adverse effect.
14. the purposes of alkali is used for making the solubilization optic yellow kind compound of the medical composition that comprises at least a A1 vitamin group chemical compound, main solvent and cosolvent to reach chemically stable by salify.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0216017 | 2002-12-17 | ||
| FR0216017A FR2848451B1 (en) | 2002-12-17 | 2002-12-17 | PROCESS FOR THE CHEMICAL STABILIZATION OF A SOLUBILIZED RETINOID AND AQUEOUS COMPOSITION OBTAINED BY THE PROCESS COMPRISING AT LEAST ONE RETINOID IN SALIVED FORM |
| US60/437,000 | 2002-12-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1728983A true CN1728983A (en) | 2006-02-01 |
Family
ID=32338901
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2003801066839A Pending CN1728983A (en) | 2002-12-17 | 2003-12-16 | Process for the chemical stabilization of a solubilized retinoid in a solvent using a base |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1728983A (en) |
| AR (1) | AR042498A1 (en) |
| FR (1) | FR2848451B1 (en) |
| ZA (1) | ZA200505124B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103543252A (en) * | 2012-07-10 | 2014-01-29 | 通用汽车环球科技运作有限责任公司 | Systems and methods for determining a state of deterioration of engine oil using multiple preselected oil properties |
| CN104507471A (en) * | 2012-06-01 | 2015-04-08 | 盖尔德马研究及发展公司 | Topical compositions in the form of a gel containing a particular solubilised retinoid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2601670B1 (en) * | 1986-07-17 | 1988-10-07 | Cird | NOVEL AROMATIC BICYCLIC DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR USE IN HUMAN AND VETERINARY MEDICINE AND IN COSMETICS |
| FR2647015B1 (en) * | 1989-05-17 | 1994-05-06 | Cird | AQUEOUS GEL BASED ON RETINOIC ACID AND ITS USE IN HUMAN MEDICINE AND COSMETICS |
| ZA954599B (en) * | 1994-06-07 | 1996-01-26 | Allergan Inc | Stable gel formulation for topical treatment of skin conditions |
| FR2731706B1 (en) * | 1995-03-14 | 1997-04-11 | Cird Galderma | AROMATIC HETEROCYCLIC COMPOUNDS, PHARMACEUTICAL AND COSMETIC COMPOSITIONS CONTAINING THEM AND USES |
| JP4061015B2 (en) * | 2000-10-30 | 2008-03-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Drug-containing composition having retinoic acid receptor agonistic action |
-
2002
- 2002-12-17 FR FR0216017A patent/FR2848451B1/en not_active Expired - Fee Related
-
2003
- 2003-12-16 CN CNA2003801066839A patent/CN1728983A/en active Pending
- 2003-12-17 AR ARP030104669A patent/AR042498A1/en not_active Application Discontinuation
-
2005
- 2005-06-24 ZA ZA200505124A patent/ZA200505124B/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104507471A (en) * | 2012-06-01 | 2015-04-08 | 盖尔德马研究及发展公司 | Topical compositions in the form of a gel containing a particular solubilised retinoid |
| CN104507471B (en) * | 2012-06-01 | 2017-08-08 | 盖尔德马研究及发展公司 | The topical composition in gel form of specific biostearin comprising dissolving |
| CN103543252A (en) * | 2012-07-10 | 2014-01-29 | 通用汽车环球科技运作有限责任公司 | Systems and methods for determining a state of deterioration of engine oil using multiple preselected oil properties |
| CN103543252B (en) * | 2012-07-10 | 2016-09-28 | 通用汽车环球科技运作有限责任公司 | Use multiple oil nature being pre-selected to determine the system and method for the status degenerativus of engine oil |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200505124B (en) | 2007-03-28 |
| AR042498A1 (en) | 2005-06-22 |
| FR2848451A1 (en) | 2004-06-18 |
| FR2848451B1 (en) | 2007-01-12 |
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