CN114767624A - Pharmaceutical composition containing 4-butoxy-beta-piperidyl propiophenone compound and preparation method and application thereof - Google Patents
Pharmaceutical composition containing 4-butoxy-beta-piperidyl propiophenone compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN114767624A CN114767624A CN202210504738.6A CN202210504738A CN114767624A CN 114767624 A CN114767624 A CN 114767624A CN 202210504738 A CN202210504738 A CN 202210504738A CN 114767624 A CN114767624 A CN 114767624A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- butoxy
- piperidyl
- oil phase
- beta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- -1 4-butoxy-beta-piperidyl propiophenone compound Chemical class 0.000 title claims description 12
- 239000003814 drug Substances 0.000 claims abstract description 35
- 230000004064 dysfunction Effects 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 239000006071 cream Substances 0.000 claims description 12
- 239000003995 emulsifying agent Substances 0.000 claims description 12
- 239000003906 humectant Substances 0.000 claims description 12
- 239000003755 preservative agent Substances 0.000 claims description 11
- 230000002335 preservative effect Effects 0.000 claims description 11
- 239000008213 purified water Substances 0.000 claims description 11
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 10
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- AXZMJZYKNWKCAH-UHFFFAOYSA-N 3-(4-butoxypiperidin-1-yl)-1-phenylpropan-1-one hydrochloride Chemical group Cl.C1CC(OCCCC)CCN1CCC(=O)C1=CC=CC=C1 AXZMJZYKNWKCAH-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 5
- 229960000541 cetyl alcohol Drugs 0.000 claims description 5
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 5
- 229940057995 liquid paraffin Drugs 0.000 claims description 5
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 5
- 239000003871 white petrolatum Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 229960004926 chlorobutanol Drugs 0.000 claims description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- 229960004063 propylene glycol Drugs 0.000 claims description 2
- 238000010298 pulverizing process Methods 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 229960003885 sodium benzoate Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229960004274 stearic acid Drugs 0.000 claims description 2
- 229940012831 stearyl alcohol Drugs 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 4
- 239000012752 auxiliary agent Substances 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000008055 phosphate buffer solution Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 19
- 206010067484 Adverse reaction Diseases 0.000 abstract description 12
- 230000006838 adverse reaction Effects 0.000 abstract description 12
- 238000005516 engineering process Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 description 16
- 230000000694 effects Effects 0.000 description 14
- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 description 9
- 229960005217 dapoxetine Drugs 0.000 description 9
- 206010036596 premature ejaculation Diseases 0.000 description 9
- 229960000385 dyclonine Drugs 0.000 description 7
- BZEWSEKUUPWQDQ-UHFFFAOYSA-N dyclonine Chemical compound C1=CC(OCCCC)=CC=C1C(=O)CCN1CCCCC1 BZEWSEKUUPWQDQ-UHFFFAOYSA-N 0.000 description 7
- KNZADIMHVBBPOA-UHFFFAOYSA-N dyclonine hydrochloride Chemical compound [Cl-].C1=CC(OCCCC)=CC=C1C(=O)CC[NH+]1CCCCC1 KNZADIMHVBBPOA-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000001647 drug administration Methods 0.000 description 5
- 229940000406 drug candidate Drugs 0.000 description 5
- 229960003462 dyclonine hydrochloride Drugs 0.000 description 5
- 239000003777 experimental drug Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XQGNETVIUOQWJW-UHFFFAOYSA-N 3-(4-butoxypiperidin-1-yl)-1-phenylpropan-1-one Chemical class C1CC(OCCCC)CCN1CCC(=O)C1=CC=CC=C1 XQGNETVIUOQWJW-UHFFFAOYSA-N 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 4
- 208000021473 Ejaculation disease Diseases 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000001568 sexual effect Effects 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000011505 plaster Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000013022 formulation composition Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 206010049244 Ankyloglossia congenital Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010037083 Prurigo Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 241001263989 Wikstroemia Species 0.000 description 1
- OPXFZJLGAZHBMA-UHFFFAOYSA-N [[1-(carbamothioylhydrazinylidene)-3-(1,3-dioxoisoindol-2-yl)butan-2-ylidene]amino]thiourea Chemical compound C1=CC=C2C(=O)N(C(C)C(C=NNC(N)=S)=NNC(N)=S)C(=O)C2=C1 OPXFZJLGAZHBMA-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960005274 benzocaine Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 238000001839 endoscopy Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
Abstract
The invention discloses a pharmaceutical composition containing a 4-butoxy-beta-piperidyl phenylpropanone compound, which is prepared by taking a 4-butoxy-beta-piperidyl phenylpropanone compound or other pharmaceutically acceptable salts as active ingredients and adding conventional auxiliaries. The invention also discloses a preparation method and application of the pharmaceutical composition. The medicine composition of the invention is obviously different from other products of known technology, the administration route is changed from oral administration to local administration, the adverse reaction brought by oral administration is greatly reduced, and a brand new clinical application is provided at the same time, and the medicine composition is applied to the treatment of male ejaculation dysfunction.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation composition for treating male ejaculatory dysfunction; in particular to a pharmaceutical composition containing 4-butoxy-beta-piperidyl phenylpropanone compounds and a preparation method and application thereof.
Background
According to the survey report of regional behavior and sexual satisfaction in Asia-Pacific region in 2013, the incidence rate of Premature Ejaculation (PE) in male ejaculation dysfunction reaches 32%, the total number of adult men in China is 4.6 hundred million, that is, more than 1.5 hundred million premature ejaculation patients exist in China. The results of a cross-sectional study conducted in 5 cities of Anhui province in China show that: in china, 34.62% of men complain of problems with premature ejaculation. Premature Ejaculation (PE) is the most common sexual dysfunction disease of men, seriously affects the sexual life quality of patients, causes family discordance and even causes psychological diseases.
At present, the domestic PE treatment medicine is mainly dapoxetine hydrochloride, and dapoxetine is the first and the only approved medicine for ejaculation dysfunction. Dapoxetine is an oral preparation, needs to be taken according to the usage amount specified in the specification and a specific time and a specific mode, is sometimes obviously limited by the environment of part of patients or the objective conditions of unsuitable oral administration and the like, is inconvenient for the patients to take the treatment medicine in time, and cannot achieve the effective treatment effect. Dapoxetine is clearly required to be taken in a cup of water in the specification, so that the user is very inconvenient. In addition, dapoxetine is orally taken, and compared with an external local administration preparation, the oral administration medicine brings great risk adverse reaction and is not beneficial to the health of patients.
The arone local anesthetic has the advantages of strong anesthesia depth, quick response (2-10min), long action time, strong penetrating power to mucous membrane, sterilization effect, lower toxicity than cocaine and benzocaine, suitability for surface anesthesia, and effects of relieving pain, relieving itching and resisting bacteria on skin. The preparation formulations used in clinical practice in China at present comprise various preparation formulations such as compound ointment, compound cream, compound solution and single-component mucilage which are prepared by combining dyclonine and other medicines, and are mainly used for various indications such as burn, abrasion, prurigo, digestive tract anesthesia and the like. The dyclonine has little absorption after being applied topically, and LD50 reaches 201mg/kg after being applied subcutaneously to rats, so the dyclonine has high safety.
Patent CN111297893A provides a compound indomethacin dyclonine plaster with water-proof property, which comprises a water-proof layer, a base cloth layer and a plaster layer, wherein the plaster layer comprises dyclonine medicine, and does not provide specific use. CN101342174A provides a compound topical preparation of ftibamzone/dyclonine and a preparation method thereof, which are used for treating herpes simplex and herpes zoster dermatosis and do not relate to the clinical application and treatment of male ejaculation disorder. CN106692036A provides a preparation method of a temperature-sensitive dyclonine hydrochloride gel, the gel prepared by the method is used for larynx anesthesia and lubrication during upper gastrointestinal endoscopy, and clinical application and treatment of male ejaculation disorder are not involved. No products containing dyclonine and clinically applied to male ejaculatory disorders are currently found on the market.
Disclosure of Invention
The invention aims to provide a topical preparation composition containing dyclonine hydrochloride, which can treat male ejaculation dysfunction, namely a pharmaceutical composition containing a 4-butoxy-beta-piperidyl propiophenone compound.
It is another object of the present invention to provide a method for preparing the above external preparation composition.
It is another object of the present invention to provide the use of the formulation composition for the treatment of male ejaculatory disorders.
The preparation composition provided by the invention is externally applied and locally administered, and the dosage form is cream. The preparation composition is obviously different from other products of known technology, the administration route is changed from oral administration to local administration, the adverse reaction caused by oral administration is greatly reduced, and simultaneously, a brand new clinical application is provided, and the preparation composition is applied to the treatment of male ejaculation dysfunction.
The technical scheme of the invention is as follows:
the invention provides a local preparation composition (containing a 4-butoxy-beta-piperidyl phenylpropanone compound) with stable quality and simple preparation, and the preparation composition preparation is smeared on a treatment part, has quick response and long effective time, and is greatly convenient for patients to use. The preparation composition is applied to the treatment of male ejaculation dysfunction, and has definite curative effect.
The pharmaceutical composition containing the 4-butoxy-beta-piperidyl propiophenone compound is in a cream form, and the administration route is external local administration; the pharmaceutical composition is prepared by taking 4-butoxy-beta-piperidyl phenylpropanone compounds or other pharmaceutically acceptable salts as active ingredients and adding conventional auxiliaries.
The active ingredient is preferably 4-butoxy-beta-piperidyl propiophenone hydrochloride (dyclonine hydrochloride).
Dyclonine hydrochloride (Dyclonine hydrochloride), the chemical name of which is 4-butoxy-beta-piperidyl propiophenone hydrochloride, is a local anesthetic with quick response, long action time, small adverse reaction and high safety.
[ chemical structural formula ]:
[ molecular formula ]: c18H28ClNO2
[ molecular weight ]: 325.87
[ CAS number ]: 536-43-6
[ basic properties ]: the product is white or quasi-white powder, and has no hygroscopicity; it is readily soluble in methanol, soluble in ethanol, sparingly soluble in water, and slightly soluble in acetone.
A pharmaceutical composition containing 4-butoxy-beta-piperidyl phenylpropanone compound comprises active component of 4-butoxy-beta-piperidyl phenylpropanone compound or other pharmaceutically acceptable salt, humectant, solid in oil phase component, consistency regulator, emulsifier, pH regulator, antiseptic and purified water.
The weight percentage of the 4-butoxy-beta-piperidyl propiophenone hydrochloride is 0.5-1%, the solid content of the oil phase is 10-15%, the consistency regulator is 15-30%, the humectant is 3-10%, the emulsifier is 0.5-5%, the pH regulator is proper, the preservative is 0.05-1%, and the balance is purified water.
Further, the oil phase in the oil phase solid component is selected from one or more of stearic acid, glyceryl monostearate, cetyl alcohol, stearyl alcohol and the like, wherein the glyceryl monostearate and the cetyl alcohol are preferred.
Further, the consistency regulator is selected from one or more of white vaseline, liquid paraffin and propylene glycol, wherein the white vaseline and the liquid paraffin are preferred.
Further, the humectant is selected from one or two of glycerin, propylene glycol and the like.
Further, the emulsifier is selected from one or two of sodium dodecyl sulfate and tween-80.
Further, the pH regulator is selected from one or more of hydrochloric acid, sodium hydroxide and phosphate buffer.
Further, the preservative is selected from one or more of chlorobutanol, sodium benzoate and ethylparaben.
A preparation method of a pharmaceutical composition containing 4-butoxy-beta-piperidyl propiophenone compounds comprises the following steps:
the first step is as follows: pulverizing active ingredient such as 4-butoxy- β -piperidyl propiophenone hydrochloride to less than 10 μm;
the second step is that: dissolving and uniformly mixing the solid and the consistency regulator in the oil phase component according to the prescription amount at 70-85 ℃ to prepare an oil phase;
the third step: taking the emulsifier, the humectant and the preservative according to the prescription amount, adding purified water, uniformly mixing, heating to 70-85 ℃, and stirring until the emulsifier, the humectant and the preservative are completely dissolved; adding a prescription amount of 4-butoxy-beta-piperidyl propiophenone hydrochloride into purified water, heating to 60-65 ℃ for complete dissolution, adding a pH regulator to regulate the pH of the main drug solution to 3.5-4.0, and uniformly mixing the two solutions to obtain a water phase;
the fourth step: and adding the water phase into the oil phase at the temperature of 60-80 ℃, stirring while inverting, and condensing to form paste to obtain a final finished product.
The 4-butoxy-beta-piperidyl propiophenone hydrochloride medicinal composition of a cream dosage form is prepared by the invention, and the problem that an oral preparation is inconvenient to use in a specific environment is solved.
The application of any one of the pharmaceutical compositions containing the 4-butoxy-beta-piperidyl propiophenone compound in preparing a medicament for treating male ejaculatory dysfunction.
Compared with the prior art, the invention has the following advantages:
1. the pharmaceutical composition containing the 4-butoxy-beta-piperidyl phenylpropanone compound provided by the invention has clinical application in treating male ejaculation disorder, in particular to the treatment application in treating male ejaculation disorder (PE);
2. the dosage form of the pharmaceutical composition provided by the invention is cream, and compared with other oral preparations for treating PE, the pharmaceutical composition directly acts on skin mucosa, and has quick response and long-lasting time;
3. the medicinal composition of the cream dosage form provided by the invention does not directly enter blood, so that the side effects caused by medicaments can be greatly reduced, the adverse reaction is low, and the safety is high;
4. the pharmaceutical composition provided by the invention is an external cream, does not need to be taken with water, can be conveniently used by patients who are inconvenient to take orally, and is more suitable for being used in the scene of therapeutic application of the product;
5. the pharmaceutical composition provided by the invention can effectively improve male ejaculation dysfunction symptoms, and has a definite clinical treatment effect.
Detailed Description
The present invention will be described in detail with reference to examples.
All of the following examples were prepared using the following method:
the first step is as follows: 4-butoxy-beta-piperidyl propiophenone hydrochloride is crushed to be less than 10 micrometers;
the second step is that: dissolving solid and consistency regulator such as white vaseline, cetyl alcohol, liquid paraffin and glyceryl monostearate in oil phase at 70-85 deg.C, and mixing to obtain oil phase;
the third step: taking the emulsifier, the humectant and the preservative according to the prescription amount, adding purified water, mixing uniformly, heating to 70-85 ℃, and stirring until the emulsifier, the humectant and the preservative are dissolved completely; adding a prescription amount of 4-butoxy-beta-piperidyl propiophenone hydrochloride into purified water, heating to 60-65 ℃ for complete dissolution, adding a pH regulator to regulate the pH of the main drug solution to 3.5-4.0, and uniformly mixing the two solutions to obtain a water phase;
the fourth step: adding the water phase into the oil phase at 60-80 ℃, stirring while chamfering, and condensing into cream paste to obtain the final product.
The formulation ratios of examples 1-5 are shown in the following table:
TABLE 1
Example 1
A pharmaceutical composition containing 4-butoxy-beta-piperidyl phenylpropanone compounds comprises the following components:
TABLE 2
The composition thereof was prepared according to the above preparation method.
The recipes of embodiments 2 to 5 are not repeated here as shown in table 1, please refer to the preparation methods shown above table 1.
Test example 1
In order to verify the stability of the pharmaceutical composition in the embodiment of the invention in an abnormal environment, the cream preparations prepared in the embodiments 1-5 are taken, and a high-temperature influence factor test and an accelerated stability investigation are performed, wherein the specific investigation results are as follows:
TABLE 3
In summary, based on the results of the impression factor examination tests of examples 1 to 5, the samples of examples 1 and 3 were found to have the best stability, and example 3 was selected as the best formulation composition in consideration of the clinical therapeutic concentration, and the pharmaceutical composition was prepared according to the formulation and preparation method of example 3 and used in clinical trials to examine the therapeutic effect.
Test example 2
The clinical treatment effect observation of the pharmaceutical composition containing the 4-butoxy-beta-piperidyl propiophenone compound.
The purpose of the test is as follows:
the clinical efficacy of the 4-butoxy-beta-piperidyl propiophenone pharmaceutical composition on male ejaculatory dysfunction is observed.
The material and the method are as follows:
1. sources of drugs
Control drug: dapoxetine hydrochloride tablet (BILITHI), 30mg standard, produced by Berlin-Chemie AG;
test drugs: the 4-butoxy- β -piperidyl propiophenone cream formulation (i.e., example 3), 1% specification, supplied by Nanjing Wikstroemia science and technology, Inc.
2. Test protocol
Patients meeting case selection criteria (the ejaculation latency is less than 1 minute) are selected and divided into two groups, one group is orally taken as a reference drug dapoxetine hydrochloride tablet and is defined as a reference drug group, and the other group is externally applied with a 4-butoxy-beta-piperidyl phenylpropanone cream preparation and is defined as a trial drug group. 19 cases of the control drug group and 18 cases of the experimental drug group, and two groups have no statistical difference in case number, age and disease age.
The contrast medicine is taken about 1-3 hours before sexual life according to the usage requirement of the dapoxetine hydrochloride tablet specification, the single dose is 30mg, at least one whole cup of water is taken for administration, and the treatment effect is evaluated after 6 treatment doses.
The experimental medicine group requires that the medicine is administered 30 minutes to 1 hour before sexual life, is smeared on the whole penis skin, the glans surface, the coronary sulcus, the prepuce frenulum and other parts, is smeared uniformly to be a thin layer, and evaluates the treatment effect after 6 times of treatment dosage.
Observation index
The evaluation is carried out from three aspects of clinical compliance, clinical treatment effect and clinical adverse reaction.
Clinical compliance: the drug administration method mainly comprises convenience of drug administration modes, drug administration feeling, privacy requirements of patients on the drug administration modes and the like, wherein the drug administration method is calculated by self-scoring of the patients, more than 85 points is excellent, 60-85 points are good, and less than 60 points is common.
The clinical treatment effect is as follows: the ejaculation latency time is effectively prolonged by more than or equal to 4 minutes by taking the ejaculation latency time extension time as a standard, the ejaculation latency time is improved by 3 to 4 minutes, and the ejaculation latency time is ineffective by less than or equal to 2 minutes.
Clinical adverse reactions: the clinical reaction of the tested person after feedback administration is taken as a standard, the adverse reaction comprises all symptoms such as headache, dizziness, sweating, skin burning, stabbing pain and the like, and the proportion of the number of people with the adverse reaction is taken as a comparison index.
Test results
The results of 6 dosing trials over four weeks of the trial were as follows:
1. clinical compliance
The clinical compliance of the control and trial drug groups is compared as shown in the table below.
TABLE 4
And (4) conclusion: compared with a test medicine group, the contrast medicine requires at least one big cup of water to be taken, and needs to be taken at least 1-3 hours in advance, so that the requirement on time environment is harsh, and the body feeling is not good for many people taking the big cup of water.
2. Clinical therapeutic effect
The clinical treatment effects of the control drug group and the experimental drug group are compared as shown in the following table.
TABLE 5
And (4) conclusion: the effective rate ratios of the two medicines are basically similar, the improvement rate of the experimental medicine group is higher than that of the control medicine group, and the clinical treatment effect of the experimental medicine group is not lower than that of the control medicine group through comprehensive comparison.
3. Adverse clinical reactions
The clinical adverse reactions of the control drug group and the experimental drug group are shown in the following table.
TABLE 6
And (4) conclusion: the adverse reactions of the control drug group, which are similar to nausea, dizziness and the like, which are frequently caused by oral drugs are obviously higher than those of the experimental drug group due to oral administration, and only 1 case of the experimental drug group reports that the skin is burnt.
Comprehensive evaluation
In conclusion, the clinical test results show that the 4-butoxy-beta-piperidyl propiophenone pharmaceutical composition provided by the invention has basically similar treatment effects to those of dapoxetine hydrochloride (bikini) on the market when treating ejaculatory dysfunction, but has better clinical administration compliance and lower adverse reaction rate.
Claims (8)
1. The pharmaceutical composition containing the 4-butoxy-beta-piperidyl phenylpropanone compound is characterized in that the pharmaceutical composition is in a form of cream, and the administration route is external local administration; the pharmaceutical composition is prepared by taking a 4-butoxy-beta-piperidyl propiophenone compound or other pharmaceutically acceptable salts as an active ingredient and adding a conventional auxiliary agent.
2. The pharmaceutical composition containing a 4-butoxy- β -piperidyl propiophenone compound according to claim 1 wherein the active ingredient is 4-butoxy- β -piperidyl propiophenone hydrochloride.
3. The pharmaceutical composition containing the 4-butoxy- β -piperidyl propiophenone compound according to claim 1 or 2, wherein the pharmaceutical composition comprises 0.5 to 1% of the active ingredient, 10 to 15% of the solid component of the oil phase, 15 to 30% of the consistency regulator, 3 to 10% of the humectant, 0.5 to 5% of the emulsifier, 0.05 to 1% of the preservative, and the balance purified water, by weight.
4. The pharmaceutical composition containing the 4-butoxy- β -piperidyl phenylpropanone compound as claimed in claim 3, wherein the oil phase in the oil phase solid component is one or more of stearic acid, glyceryl monostearate, cetyl alcohol, stearyl alcohol and the like;
the consistency regulator is one or more of white vaseline, liquid paraffin and propylene glycol;
the humectant is one or two of glycerol, propylene glycol and the like;
the emulsifier is one or two of sodium dodecyl sulfate and tween-80;
the pH regulator is one or more of hydrochloric acid, sodium hydroxide and phosphate buffer solution;
the preservative is one or more of chlorobutanol, sodium benzoate and ethylparaben.
5. The pharmaceutical composition containing 4-butoxy- β -piperidyl propiophenone compound according to claim 4 wherein the oil phase of the oil phase solid component is glyceryl monostearate and cetyl alcohol; the consistency regulator is white vaseline and liquid paraffin.
6. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 5 containing a 4-butoxy- β -piperidyl propiophenone compound, which comprises:
pulverizing the active ingredients of the pharmaceutical composition to less than 10 microns;
dissolving and uniformly mixing the solid and the consistency regulator in the oil phase component according to the prescription amount to obtain an oil phase;
taking the emulsifier, the humectant and the preservative according to the prescription amount, adding purified water, mixing uniformly, and stirring until the emulsifier, the humectant and the preservative are completely dissolved to obtain a solution A; adding purified water into the active component according to the prescription amount, mixing and completely dissolving the active component, and adding a pH regulator to obtain a solution B; uniformly mixing the solution A and the solution B to obtain a water phase;
and adding the water phase into the oil phase, stirring while pouring, and condensing into paste to obtain the pharmaceutical composition.
7. The method of claim 6, wherein the reaction temperature of the solids in the oil phase ingredients and the consistency regulator is 70-85 ℃;
the reaction temperature of the emulsifier, the humectant, the preservative and the purified water is 70-85 ℃;
the reaction temperature of the active ingredients and the purified water is 60-65 ℃, and a pH regulator is added to regulate the pH to 3.5-4.0;
the reaction temperature of adding the water phase into the oil phase is 60-80 ℃.
8. Use of a pharmaceutical composition comprising a 4-butoxy- β -piperidinyl propiophenone compound according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of male ejaculatory dysfunction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210504738.6A CN114767624A (en) | 2022-05-10 | 2022-05-10 | Pharmaceutical composition containing 4-butoxy-beta-piperidyl propiophenone compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210504738.6A CN114767624A (en) | 2022-05-10 | 2022-05-10 | Pharmaceutical composition containing 4-butoxy-beta-piperidyl propiophenone compound and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114767624A true CN114767624A (en) | 2022-07-22 |
Family
ID=82436532
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210504738.6A Pending CN114767624A (en) | 2022-05-10 | 2022-05-10 | Pharmaceutical composition containing 4-butoxy-beta-piperidyl propiophenone compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114767624A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040241245A1 (en) * | 2003-03-21 | 2004-12-02 | Nexmed (Holdings) Inc. | Compositions and methods for treatment of premature ejaculation |
| CN101342174A (en) * | 2008-08-26 | 2009-01-14 | 北京天川军威医药技术开发有限公司 | Phthiobuzonum/diclothane compound topical formulation |
| WO2011074015A2 (en) * | 2009-12-17 | 2011-06-23 | Themis Medicare Limited | Novel composition of pharmaceutical product to treat sexual dysfunction |
| CN102440946A (en) * | 2010-10-08 | 2012-05-09 | 何晓磊 | Preparation method of dyclonine ointment |
| CN107235930A (en) * | 2017-06-12 | 2017-10-10 | 常州市天华制药有限公司 | A kind of synthetic method of dyclonine hydrochloride |
-
2022
- 2022-05-10 CN CN202210504738.6A patent/CN114767624A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040241245A1 (en) * | 2003-03-21 | 2004-12-02 | Nexmed (Holdings) Inc. | Compositions and methods for treatment of premature ejaculation |
| CN1761461A (en) * | 2003-03-21 | 2006-04-19 | 奈克斯麦德控股有限公司 | Compositions and methods for treatment of premature ejaculation |
| CN101342174A (en) * | 2008-08-26 | 2009-01-14 | 北京天川军威医药技术开发有限公司 | Phthiobuzonum/diclothane compound topical formulation |
| WO2011074015A2 (en) * | 2009-12-17 | 2011-06-23 | Themis Medicare Limited | Novel composition of pharmaceutical product to treat sexual dysfunction |
| CN102440946A (en) * | 2010-10-08 | 2012-05-09 | 何晓磊 | Preparation method of dyclonine ointment |
| CN107235930A (en) * | 2017-06-12 | 2017-10-10 | 常州市天华制药有限公司 | A kind of synthetic method of dyclonine hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| GITTELMAN, M等: "Synergistic effect of meatal application of dyclonine/alprostadil cream for the treatment of early ejaculation (EE) in a double-blind and crossover study", J SEX MED, vol. 3, pages 224 - 286 * |
| 林颖苹;朱伟文;邹璇;: "复方盐酸达克罗宁乳膏佐治瘙痒性皮肤病的临床疗效分析", 中国实用医药, no. 26, pages 135 - 136 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE60022021T2 (en) | Preparations containing apomorphine and sildenafil and their use for the treatment of erectile dysfunction | |
| EP2373346B1 (en) | Ibuprofen for topical administration | |
| TWI355936B (en) | Uses of palonosetron hydrochloride | |
| JPS62292720A (en) | Release control type dihydrocodein composition | |
| KR20010078754A (en) | Methods and transdermal compositions for pain relief | |
| JPS6048921A (en) | Indomethacin-containing composition | |
| TW201244718A (en) | A pharmaceutical composition for treating a disease in the oral cavity comprising rebamipide | |
| CN102245167A (en) | Formulation for oral transmucosal administration of analgesic and/or antispasmodic molecules | |
| JPS62298530A (en) | Pharmaceutical composition for suppository | |
| JPS6259219A (en) | Antitussive, expectorant, analgesic and sedative agent for external use | |
| NO309965B1 (en) | Oral pharmaceutical anti-cough preparation | |
| CN114767624A (en) | Pharmaceutical composition containing 4-butoxy-beta-piperidyl propiophenone compound and preparation method and application thereof | |
| JPH08295637A (en) | Local administrative agent for oral cavity | |
| WO2019091082A1 (en) | Solution preparation for aerosol inhalation of carbocisteine, and preparation method therefor | |
| US20210213009A1 (en) | Methods of treating pain | |
| CN113713000B (en) | Main medicine component composition for treating sore carbuncle, burn, scald and acne, sustained and controlled release pharmaceutical preparation, and preparation method and application thereof | |
| JP2006008540A (en) | Cold remedy | |
| RU2426531C1 (en) | Liquid water pharmaceutical composition of ambroxol and pharmaceutical preparation based on it, intended for treating diseases of respiratory ways with formation of viscous sputum (versions) | |
| KR102572676B1 (en) | Pharmaceutical composition for the prevention and the treatment of respiratory deseases | |
| HU207446B (en) | Method for producing medicinal preparation of local use | |
| JP2003342186A (en) | Oral liquid formulation composition for rhinitis | |
| KR101781071B1 (en) | Composition for orally rapid disintegrating film of local anesthesia | |
| Когай et al. | Pharmacology: practical manual for students enrolled in the basic educational program of the specialty General medicine (bilingual program) | |
| JPS58164516A (en) | Remedy for eczematoid skin disease and drug rash | |
| JPH09323938A (en) | Medicine for common cold |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |