CN117442736A - Pharmaceutical composition, composite material, patch and preparation method and application thereof - Google Patents

Pharmaceutical composition, composite material, patch and preparation method and application thereof Download PDF

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Publication number
CN117442736A
CN117442736A CN202311410616.1A CN202311410616A CN117442736A CN 117442736 A CN117442736 A CN 117442736A CN 202311410616 A CN202311410616 A CN 202311410616A CN 117442736 A CN117442736 A CN 117442736A
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CN
China
Prior art keywords
parts
film
pharmaceutical composition
phloroglucinol
progesterone
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Pending
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CN202311410616.1A
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Chinese (zh)
Inventor
王晓宇
刘诚
汪洋
邓娟
周凯
符洁
黄恋清
朱小珊
胡甜
左权
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Wuhan Jiulong Humanwell Pharmaceutical Co ltd
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Wuhan Jiulong Humanwell Pharmaceutical Co ltd
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Priority to CN202311410616.1A priority Critical patent/CN117442736A/en
Publication of CN117442736A publication Critical patent/CN117442736A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The invention discloses a pharmaceutical composition, a composite material, a patch, a preparation method and application thereof. The medicine composition comprises the following components in parts by weight: 0.8-4 parts of progesterone, 1.5-10 parts of phloroglucinol, 200-1000 parts of pressure-sensitive adhesive and 6-30 parts of fatty compound. The patch provided by the invention can effectively relieve and treat dysmenorrhea and improve the quality of life of females.

Description

Pharmaceutical composition, composite material, patch and preparation method and application thereof
Technical Field
The invention particularly relates to a pharmaceutical composition, a composite material, a patch, a preparation method and application thereof.
Background
Dysmenorrhea is one of the most common conditions for teenagers and adult females, and refers to pain in the lower abdomen, distention and pain in the waist or other discomfort before and after menstruation or during menstrual period. Dysmenorrhea can be divided into primary dysmenorrhea and secondary dysmenorrhea, wherein primary dysmenorrhea refers to dysmenorrhea without organic lesions of reproductive organs; the secondary dysmenorrhea refers to dysmenorrhea caused by pelvic organic diseases, such as endometriosis, adenomyosis, etc. Primary dysmenorrhoea is common in teenagers, mostly occurs within 1-2 years after the beginner, and pain begins after menstrual onset, most severe in the first day of menstruation, and is relieved after 2-3 days. Secondary dysmenorrhea is generally dysmenorrhea that occurs years after menstruation.
Related epidemiological researches at home and abroad show that the incidence rate of primary dysmenorrhea is generally 42% -90%, wherein the incidence rate of severe dysmenorrhea accounts for 18%, so that the work and study of women are seriously affected, the quality of life is reduced, and the physical and mental health of women is seriously affected. Current methods for treating dysmenorrhea are mainly divided into three categories: (1) oral medication: although the curative effect of the nonsteroidal anti-inflammatory drug and the contraceptive is definite, the adverse reaction is more; the Chinese patent medicine has the advantages of general curative effect, slow efficacy, longer treatment period, high price, poor taste, inconvenient carrying and difficult wide acceptance, and the oral medicine has liver first pass effect and gastrointestinal tract irritation after long-term administration, thereby increasing the liver and kidney burden of the body of a patient; (2) physical therapy: including body needles, ear needles, water needles, moxibustion cupping, microwave radiation therapy, etc.; although the method takes effect quickly, the method can not treat the disease by itself, and sometimes has a lot of inconveniences; (3) surgery: surgery is often used in secondary dysmenorrhea patients and has limitations as a traumatic treatment modality. In summary, the three methods have various disadvantages in use, and do not achieve good relief effect on female menstrual abdominal pain discomfort.
Therefore, how to effectively relieve and treat dysmenorrhea and improve the quality of life of females has become an urgent problem to be solved.
Disclosure of Invention
The invention solves the technical problem that the prior art cannot effectively relieve and treat dysmenorrhea, and provides a pharmaceutical composition, a composite material, a patch, a preparation method and application thereof. The patch provided by the invention can effectively relieve and treat dysmenorrhea and improve the quality of life of females.
The invention solves the technical problems by the following technical proposal:
the invention provides a pharmaceutical composition, which comprises the following components in parts by weight:
0.8-4 parts of progesterone, 1.5-10 parts of phloroglucinol, 200-1000 parts of pressure-sensitive adhesive and 6-30 parts of fatty compound.
In the present invention, the progesterone may be one or more of progesterone, levonorgestrel, drospirenone, medroxyprogesterone acetate and norethindrone, preferably progesterone, drospirenone or levonorgestrel.
In the present invention, the progesterone is preferably used in an amount of 1 to 3 parts, for example 1 part, 1.5 parts or 2 parts.
In the present invention, the phloroglucinol is preferably used in an amount of 2 to 8 parts, for example, 2 parts, 2.5 parts, 3 parts or 4 parts, more preferably 2.5 to 7 parts.
In the present invention, the pressure-sensitive adhesive may be conventional in the art, such as a polyacrylate pressure-sensitive adhesive.
In the present invention, the pressure-sensitive adhesive is preferably used in an amount of 400 to 800 parts, for example 600 parts.
In the present invention, the fatty compound may be a fatty acid or fatty acid ester, preferably one or more of stearic acid, oleic acid, ethyl oleate and isopropyl myristate, more preferably one or more of oleic acid, ethyl oleate and isopropyl myristate.
In the present invention, the fatty compound is preferably used in an amount of 8 to 25 parts, for example, 10 parts, 15 parts, 18 parts or 20 parts.
In the present invention, the content distribution uniformity RSD% of the phloroglucinol in the pharmaceutical composition is less than 0.5%, preferably 0.21%, 0.24%, 0.25%, 0.27%, 0.30%, 0.32%, 0.33%, 0.34% or 0.39%.
In a preferred embodiment, the progesterone is progesterone and the fatty compound is oleic acid.
In a preferred embodiment, the progesterone is drospirenone and the fatty compound is isopropyl myristate.
In a preferred embodiment, the progesterone is levonorgestrel and the fatty compound is ethyl oleate.
In the present invention, the pharmaceutical composition preferably further comprises a dispersing agent. The dispersing agent may be a solvent, such as water and/or alcohol, capable of dispersing progesterone, phloroglucinol, and fatty compounds, as is conventional in the art. The water may be conventional in the art, such as deionized water. The alcohol is preferably one or more of glycerol, propylene glycol and butylene glycol.
In step (1), the dispersant may be used in an amount conventional in the art, typically in a ratio of the sum of the masses of the progesterone and the phloroglucinol to the volume of the dispersant of (5-50): 1mg/mL, preferably (5-20): 1mg/mL, for example 10:1mg/mL.
The invention also provides a composite material, which comprises the pharmaceutical composition.
The invention also provides a preparation method of the composite material, which comprises the following steps:
(1) Mixing the progesterone, the phloroglucinol, the fatty compound, the solvent and the dispersing agent to prepare a dispersion;
(2) Mixing the dispersion liquid and the solution containing the pressure-sensitive adhesive, standing until bubbles completely disappear, and drying.
In step (1), the solvent may be a solvent capable of dissolving progesterone, phloroglucinol, and fatty compounds, such as alcohols, as is conventional in the art.
Wherein the alcohol can be alkyl alcohol with 1-4 carbon atoms, such as one or more of ethanol, propanol, propylene glycol, isopropanol, glycerol and butanol.
In step (1), the solvent may be used in an amount conventional in the art, typically to dissolve the progesterone, phloroglucinol and fatty compounds, for example 50-1000 parts, preferably 50-300 parts, for example 100 parts or 200 parts.
In step (1), the dispersing agent may be a solvent capable of dispersing progesterone, phloroglucinol, and fatty compounds, such as water and/or alcohols, as is conventional in the art. The water may be conventional in the art, such as deionized water. The alcohol is preferably one or more of glycerol, propylene glycol, and butylene glycol.
In step (1), the dispersant may be used in an amount conventional in the art, typically in a ratio of the sum of the masses of the progesterone and the phloroglucinol to the volume of the dispersant of (5-30): 1mg/mL, preferably (5-20): 1mg/mL, for example 10:1mg/mL.
In step (1), the dispersion is preferably prepared by: adding the progesterone, the phloroglucinol and the fatty compound to the solvent and then to the dispersant.
In step (2), the dispersion is preferably added to a solution containing a pressure-sensitive adhesive.
In the step (2), the solvent in the solution containing the pressure-sensitive adhesive may be a solvent capable of dissolving the pressure-sensitive adhesive, which is conventional in the art, preferably one or more of dichloromethane, ethyl acetate, methanol, ethanol and isopropanol, for example, ethyl acetate.
In step (2), the preparation method of the pressure-sensitive adhesive-containing solution may be conventional in the art, and the pressure-sensitive adhesive is generally dissolved in a solvent.
In the step (2), the mass percentage of the pressure-sensitive adhesive in the solution containing the pressure-sensitive adhesive may be 10% to 50%, preferably 15% to 30%, for example 25%.
In step (2), the means of mixing may be conventional in the art, such as stirring.
Wherein the stirring time may be 10-60min, for example 20min.
Wherein the rotational speed of the stirring may be 100-1000rpm/min, e.g. 500rpm/min.
In step (2), the mixing is typically performed at room temperature.
In step (2), the mixing is generally followed by sonication.
Wherein the time of the ultrasound may be 10-60min, such as 20min, 30min or 40min.
In step (2), the drying means may be conventional in the art, such as drying.
Wherein the temperature of the drying may be 25-50 ℃, for example 40 ℃.
Wherein the drying time may be 10-30min, for example 20min.
In step (2), the drying is preceded by a standing, preferably at room temperature. The time of the rest may be 0.5-2 hours, for example 1 hour.
In the step (2), if the air bubbles are not completely removed by standing, the medicine distribution is uneven, the adhesive strength of the composite material is affected, and the appearance of the composite material is poor.
The invention also provides a patch, which comprises a protective film, the composite material and a backing film, wherein the composite material is positioned between the protective film and the backing film.
In the invention, the area of the medicine patch can be 10-50 cm 2 For example 10cm 2 、20cm 2 、30cm 2 、40cm 2 Or 50cm 2 。
In the present invention, the progesterone content on the patch is preferably 0.5-10mg/cm 2 For example 1mg/cm 2 、1.25mg/cm 2 、1.67mg/cm 2 、2.5mg/cm 2 、3.33mg/cm 2 Or 5mg/cm 2 。
In the present invention, the content of the phloroglucinol on the patch is preferably 1-20mg/cm 2 For example 3mg/cm 2 、3.33mg/cm 2 、3.75mg/cm 2 、5mg/cm 2 、6.67mg/cm 2 Or 10mg/cm 2 。
In the present invention, the protective film may be one or more of a polyethylene terephthalate film, a polyethylene film, and a polypropylene film, for example, a polyethylene terephthalate film.
In the present invention, the surface of the protective film preferably contains fluorine and/or silicon.
In the present invention, the protective film is preferably subjected to plasma treatment, fluorine-coating treatment or silicon-coating treatment before use.
In the present invention, the backing film may be one or more of polyethylene terephthalate film, polypropylene film, polyethylene film, ethylene-vinyl acetate copolymer film, and polyurethane film.
The backing film is preferably one or more layers of composite film.
The invention also provides a preparation method of the patch, which comprises the following steps:
and (3) coating the pharmaceutical composition in the composite material on the protective film, and attaching the backing film after drying.
In the present invention, the drying temperature may be 25 to 50 ℃, for example 40 ℃.
In the present invention, the drying time may be 10 to 30 minutes, for example, 20 minutes.
In the present invention, the coating is preferably performed after the drying and before the drying.
Wherein the temperature of the standing may be room temperature. The room temperature generally means 25.+ -. 5 ℃.
Wherein the time of the standing may be 0.5 to 2 hours, for example 1 hour.
The invention also provides a pharmaceutical composition as described above, or the composite material, or the application of the patch in treating dysmenorrhea.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
(1) The patch can effectively treat dysmenorrhea, has less adverse reaction, is convenient to use, is simple to prepare and has lower production cost;
(2) Compared with the traditional oral administration, the invention adopts the administration mode of the external patch, so that the medicine enters into the capillary vessel through the skin at a constant or nearly constant speed, the constant blood concentration can be maintained, and the medicine has more durable and stable curative effect; meanwhile, the medicine enters the systemic circulation through the skin or mucous membrane, and the first pass effect of the liver can be avoided, so that the medicine availability is improved, the administration dosage is reduced, and adverse reactions are reduced.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The reagents or equipment used in the following examples and comparative examples are shown in table 1:
TABLE 1
Reagents or apparatus Manufacturer or model
Progesterone (Progesterone) HUBEI GEDIAN HUMANWELL PHARMACEUTICAL Co.,Ltd.
Phloroglucinol HUBEI GEDIAN HUMANWELL PHARMACEUTICAL Co.,Ltd.
Oleic acid HUBEI GEDIAN HUMANWELL PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
Oleic acid ethyl ester HUBEI GEDIAN HUMANWELL PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
Myristic acid isopropyl ester HUBEI GEDIAN HUMANWELL PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
Ethanol HUBEI GEDIAN HUMANWELL PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
Propylene glycol HUBEI GEDIAN HUMANWELL PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
Isopropyl alcohol Hunan Er-Kang Pharmaceutical Co.,Ltd.
Polyacrylate pressure sensitive adhesive JIANGSU KANGBEIDE PHARMACEUTICAL Co.,Ltd.
Protective film 3M Co.
Backing film 3M Co.
Phloroglucinol orally disintegrating tablet Teva Sante
In the following examples and comparative examples, 50mg was regarded as one serving.
Example 1
(1) Respectively taking 1 part (50 mg) of progesterone, 3 parts (150 mg) of phloroglucinol, 10 parts (0.5 g) of oleic acid and 100 parts (5 g) of ethanol, mixing the progesterone, the phloroglucinol and the oleic acid, adding the mixture into the ethanol, adding the mixed solution into 20mL of water after mixing, and fully dispersing to obtain an aqueous dispersion;
(2) Dissolving 600 parts (30 g) of polyacrylate pressure-sensitive adhesive by using ethyl acetate to form a polyacrylate pressure-sensitive adhesive solution, wherein the polyacrylate pressure-sensitive adhesive accounts for 25% of the polyacrylate pressure-sensitive adhesive solution;
(3) Pouring the aqueous dispersion into a polyacrylate pressure-sensitive adhesive solution, stirring at room temperature for 20min at 500rpm/min, performing ultrasonic treatment for 30min after stirring, and standing until bubbles completely disappear to obtain a mixture;
(4) Uniformly coating the mixture on a protective film (polyethylene terephthalate film) subjected to plasma treatment, standing at 25deg.C for 1 hr, transferring into a 40deg.C oven, oven drying for 20min, and attaching a backing film (polyethylene terephthalate film) to obtain a film containing progesterone of 1.67mg/cm per unit area 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Example 2
Compared with example 1, the method is the same as that of example 1 except that progesterone is replaced by medroxyprogesterone acetate, oleic acid is replaced by ethyl oleate, ethanol is replaced by propylene glycol, and the unit area of medroxyprogesterone acetate is 1.67mg/cm 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Example 3
In comparison with example 1, in addition to the replacement of progesterone with drospirenone, the oil wasThe acid was replaced with isopropyl myristate and the ethanol was replaced with isopropyl alcohol, which was the same as in example 1 to obtain drospirenone in a unit area of 1.67mg/cm 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Example 4
Compared with example 1, the preparation method is the same as that of example 1 except that progesterone is replaced by levonorgestrel, oleic acid is replaced by ethyl oleate, and ethanol is replaced by propylene glycol, so that the unit area of the preparation method contains 1.67mg/cm of levonorgestrel 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Example 5
As compared with example 1, the same procedure as in example 1 was followed except that progesterone was replaced with norethindrone, oleic acid was replaced with isopropyl myristate, and ethanol was replaced with isopropyl alcohol, to obtain a norethindrone-containing fraction per unit area of 1.67mg/cm 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Example 6
Compared with example 1, except that 50mg of progesterone is replaced with 100mg of drospirenone, the dosage of phloroglucinol is adjusted to 200mg, 0.5g of oleic acid is replaced with 1g of isopropyl myristate, 5g of ethanol is replaced with 10g of glycol, the preparation method is the same as that of example 1, and the yield per unit area of drospirenone is 3.33mg/cm 2 The content of phloroglucinol is 6.67mg/cm 2 The area of the drug patch is 30cm 2 。
Example 7
As compared with example 3, the same procedures as in example 3 were repeated except that the amount of isopropyl myristate was replaced with 1.0g, to obtain drospirenone having a unit area of 1.67mg/cm 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Example 8
In comparison with example 3, the amount of phloroglucinol was replaced by 100mgHe was the same as in example 3, to obtain drospirenone having a unit area of 1.67mg/cm 2 The content of phloroglucinol is 3.33mg/cm 2 The area of the drug patch is 30cm 2 。
Example 9
As compared with example 3, the same procedures as in example 3 were repeated except that the amount of drospirenone was replaced with 100mg, to obtain a drospirenone per unit area of 3.33mg/cm 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Example 10
As compared with example 3, the same procedures as in example 3 were repeated except that the amount of phloroglucinol was increased to 300mg, to obtain drospirenone in a unit area of 1.67mg/cm 2 The content of phloroglucinol is 10mg/cm 2 The area of the drug patch is 30cm 2 。
Example 11
As compared with example 3, the same procedures as in example 3 were followed except that isopropyl myristate was changed to stearic acid, to obtain drospirenone in a unit area of 1.67mg/cm 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Comparative example 1
As compared with example 3, the same procedures as in example 3 were followed except that isopropyl myristate was removed to obtain drospirenone in a unit area of 1.67mg/cm 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Comparative example 2
As compared with example 3, the same procedures as in example 3 were repeated except that the amount of isopropyl myristate was replaced with 0.25g, to obtain drospirenone in a unit area of 1.67mg/cm 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Comparative example 3
In comparison with example 3, except that the amount of phloroglucinol was replaced with 50mgIs the same as in example 3, and the yield per unit area of drospirenone is 1.67mg/cm 2 The content of phloroglucinol is 1.67mg/cm 2 The area of the drug patch is 30cm 2 。
Comparative example 4
As compared with example 3, the same procedures as in example 3 were followed except that the amount of drospirenone was replaced with 30mg, to obtain a drospirenone per unit area of 1mg/cm 2 The content of phloroglucinol is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Comparative example 5
Phloroglucinol orally disintegrating tablets (Teva Sante).
Comparative example 6
As compared with example 3, the same procedures as in example 3 were followed except that phloroglucinol was changed to mebeverine hydrochloride (phloroglucinol analog), to obtain drospirenone in a unit area of 1.67mg/cm 2 The content of phloroglucinol analogues is 5mg/cm 2 The area of the drug patch is 30cm 2 。
Effect example 1: therapeutic effect of medicine patch on relieving dysmenorrhea
1. Patient group entry criteria
Patients were self-rated daily for pain rating during menstruation, and patients with pain averages above 3 levels during menstrual period were selected into groups.
The World Health Organization (WHO) divides pain levels into:
level 0: pain-free;
stage 1: mild pain, intermittent pain, may be without medication;
2 stages: moderate pain, persistent pain, affecting rest, pain-relieving drugs are needed;
3 stages: severe pain, persistent pain, cannot be relieved without medication;
4 stages: severe pain is persistent severe pain accompanied by changes in blood pressure, pulse, etc.
2. Test drug
Test drug: the drug patches prepared in examples 1-11;
control drug: the drug patches prepared in comparative examples 1-4 and comparative example 6, the phloroglucinol orally disintegrating tablet (Teva Sante) of comparative example 5.
3. Experimental grouping
204 dysmenorrhea patients were screened according to the group entry criteria, randomly assigned to 17 groups of 12 persons each, and assigned to 6 control groups and 11 test groups.
4. Administration method
Test groups 1-11 were given 1 drug patch of examples 1-11, respectively, only 1 day prior to menstruation; the control groups 1-4, 6 were given 1 drug patch of comparative examples 1-4, 6, respectively, only 1 day prior to menstruation; control 5 phloroglucinol orally disintegrating tablet of control 5 was administered once daily from day 1 before menstruation to day 3 of the menstrual cycle.
Note that: in the using process, the medicine patches of the test groups 1-11 and the control groups 1-4 and 6 are placed near the navel; the drug of control group 5 was orally administered.
5. Observation index
The patients are subjected to pain visual simulation scoring before and after treatment, the dysmenorrhea symptoms and pain degree of the patients are evaluated, and experimental data acquisition work is completed.
Pain visual simulation score (VAS score): a line segment with the length of 10cm is drawn on the paper, and the line segments are marked from 0 to 10 in sequence. Scale 0 indicates no pain and scale 10 indicates the most severe pain that can be imagined; grade 1-3 indicates mild pain, but still can engage in normal activity; grade 4-6 indicates moderate pain, affects work, but can give birth to oneself; grade 7-9 indicates severe pain and the life cannot be self-care; scale 10 indicates severe pain and intolerance.
6. Treatment efficacy determination
Efficacy index = (pre-treatment VAS score-post-treatment VAS score)/(pre-treatment VAS score) ×100%
The effect is shown: the curative effect index is more than or equal to 70%;
the method is effective: the curative effect index is more than or equal to 30 percent;
invalidation: the curative effect index is less than 30%;
effective rate= (effective number + effective number)/total number of people.
7. Test results
The test results show that: the test drug has significantly improved efficacy over the control drug (see table 2).
TABLE 2
Grouping Headcount of people Has obvious effect Effective and effective Effective rate of
Example 1 12 1 6 58.3％
Example 2 12 0 5 41.7％
Example 3 12 1 7 66.7％
Example 4 12 1 6 58.3％
Example 5 12 0 6 50.0％
Example 6 12 1 8 75.0％
Example 7 12 2 6 66.7％
Example 8 12 1 5 50.0％
Example 9 12 1 6 58.3％
Example 10 12 3 5 66.7％
Example 11 12 0 5 41.7％
Comparative example 1 12 1 0 8.3％
Comparative example 2 12 2 1 25.0％
Comparative example 3 12 1 0 8.3％
Comparative example 4 12 1 0 8.3％
Comparative example 5 12 1 2 33.3％
Comparative example 6 12 0 3 25％
According to experimental results, the medicine patches prepared in the examples 1-11 can effectively treat dysmenorrhea, reduce the administration dosage and the administration times, improve the compliance of patients, and have better effect of treating dysmenorrhea than the phloroglucinol orally disintegrating tablets which are marketed.
The drug patch prepared in comparative example 1 had very poor effect of treating dysmenorrhea because no fatty compound was added.
The drug patch prepared in comparative example 2 was poor in effect of treating dysmenorrhea due to too small amount of fatty compound.
The drug patch prepared in comparative example 3 was poor in effect of treating dysmenorrhea due to too small amount of phloroglucinol.
The drug patch prepared in comparative example 4 was poor in effect of treating dysmenorrhea due to too small amount of progesterone.
The drug patch prepared in comparative example 6 was poor in effect of treating dysmenorrhea due to the use of phloroglucinol analogues.
Effect example 2 in vitro percutaneous permeation rate determination:
the prepared patch is covered on the cuticle of the skin of a nude mouse, and is clamped between a receiving tank and a sample tank of a Franz vertical diffusion tank, and the dermis layer of the skin faces the receiving tank. The temperature was maintained at 37 ℃, the receiving medium was normal saline and skin spoilage was avoided by adding sodium penicillin to the medium. Samples were taken at 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72 hours, the concentrations of the samples were measured by ultraviolet spectroscopy, a graph of cumulative transdermal release amount of the drug versus time was drawn, the type of release profile of the drug from each test group sample was judged according to the cumulative transdermal release amount versus time linear regression equation over 12-72 hours, and the average transdermal permeation rate of each test group sample over 72 hours was calculated as shown in table 3.
TABLE 3 average transdermal penetration rates of the patches of examples 1-11 and comparative examples 1-4, 6 over 72 hours
Note that: zero order release refers to a release where the release rate of the pharmaceutically active ingredient does not change over time, i.e. the rate remains constant during the release period of the pharmaceutically active ingredient.
If the average transdermal penetration rate of the patch is too low for the patient, the intended therapeutic effect will not be achieved, even without any therapeutic effect. The average transdermal penetration rate of the patches in examples 1 to 11 of the present invention was not less than 31.37. Mu.g cm -2 *h -1 Up to 67.92 μg cm -2 *h -1 Can meet the daily required administration dosage of patients and has excellent treatment effect.
Effect example 3 content uniformity test
And removing the anti-adhesive layers of the prepared samples respectively, uniformly dividing the samples into small blocks of 5*5, and placing the small blocks in a conical flask. Adding methanol for soaking and ultrasonic treatment to dissolve the sample completely, and filtering with filter membrane to obtain the sample to be detected. The peak areas of phloroglucinol for each sample were detected and recorded in a high performance liquid chromatograph, and the results are shown in table 4.
TABLE 4 Table 4
According to experimental results, the RSD% of the drug patches prepared in examples 1-11 after being divided into small pieces is less than 0.5%, and the content is relatively uniform, which indicates that the dispersibility of the prepared samples is relatively good.

Claims (10)

1. A pharmaceutical composition, characterized in that it comprises, in parts by weight:
0.8-4 parts of progesterone, 1.5-10 parts of phloroglucinol, 200-1000 parts of pressure-sensitive adhesive and 6-30 parts of fatty compound.
2. The pharmaceutical composition of claim 1, wherein the content distribution uniformity rsd% of the phloroglucinol in the pharmaceutical composition is less than 0.5%;
and/or, the progesterone is one or more of progesterone, levonorgestrel, drospirenone, medroxyprogesterone acetate and norethindrone, preferably progesterone, drospirenone or levonorgestrel;
and/or the progesterone is used in an amount of 1-3 parts, e.g., 1 part, 1.5 parts, or 2 parts.
3. Pharmaceutical composition according to claim 1 or 2, wherein the phloroglucinol is used in an amount of 2-8 parts, such as 2 parts, 2.5 parts, 3 parts or 4 parts, preferably 2.5-7 parts;
and/or the pressure-sensitive adhesive is polyacrylate pressure-sensitive adhesive;
and/or the pressure sensitive adhesive is used in an amount of 400 to 800 parts, for example 600 parts.
4. Pharmaceutical composition according to claim 1 or 2, wherein the fatty compound is a fatty acid or fatty acid ester, preferably one or more of stearic acid, oleic acid, ethyl oleate and isopropyl myristate, more preferably one or more of oleic acid, ethyl oleate and isopropyl myristate;
and/or the fatty compound is used in an amount of 8-25 parts, for example 10 parts, 15 parts, 18 parts or 20 parts;
and/or, the pharmaceutical composition further comprises a dispersing agent;
preferably, the dispersant is water and/or an alcohol.
5. A composite material, characterized in that it comprises a pharmaceutical composition according to any one of claims 1-4.
6. A method of preparing the composite material of claim 5, comprising the steps of:
(1) Mixing the progesterone, the phloroglucinol, the fatty compound, the solvent and the dispersing agent to prepare a dispersion;
(2) Mixing the dispersion liquid and the solution containing the pressure-sensitive adhesive, standing until bubbles completely disappear, and drying.
7. The method of preparing a composite material according to claim 6, wherein the solvent is an alcohol;
preferably, the alcohol is an alkyl alcohol having 1 to 4 carbon atoms, such as one or more of ethanol, propanol, propylene glycol, isopropanol, glycerol and butanol;
and/or the solvent is used in an amount of 50 to 1000 parts, preferably 50 to 300 parts, for example 100 parts or 200 parts;
and/or the dispersant is water and/or alcohol;
and/or the ratio of the sum of the masses of the progesterone and the phloroglucinol to the volume of the dispersant is (5-30): 1mg/mL, preferably (5-20): 1mg/mL, for example 10:1mg/mL;
and/or the mass percentage of the pressure-sensitive adhesive in the solution containing the pressure-sensitive adhesive is 10-50%, preferably 15-30%, for example 25%.
8. A patch comprising a protective film, the composite of claim 5, and a backing film, the composite being positioned between the protective film and the backing film;
preferably, the protective film is one or more of polyethylene terephthalate film, polyethylene film and polypropylene film, such as polyethylene terephthalate film;
preferably, the backing film is one or more of polyethylene terephthalate film, polypropylene film, polyethylene film, ethylene-vinyl acetate copolymer film, and polyurethane film.
9. A method of preparing the patch of claim 8, comprising the steps of:
and (3) coating the pharmaceutical composition in the composite material on the protective film, and attaching the backing film after drying.
10. Use of a pharmaceutical composition according to any one of claims 1-4, or a composite according to claim 5, or a patch according to claim 8, for the treatment of dysmenorrhea.
CN202311410616.1A 2023-10-27 2023-10-27 Pharmaceutical composition, composite material, patch and preparation method and application thereof Pending CN117442736A (en)

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