CN114732802A - Netixinong transdermal patch - Google Patents
Netixinong transdermal patch Download PDFInfo
- Publication number
- CN114732802A CN114732802A CN202210417121.0A CN202210417121A CN114732802A CN 114732802 A CN114732802 A CN 114732802A CN 202210417121 A CN202210417121 A CN 202210417121A CN 114732802 A CN114732802 A CN 114732802A
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- CN
- China
- Prior art keywords
- nitisinone
- transdermal
- layer
- sensitive adhesive
- adhesive matrix
- 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.)
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Classifications
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- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Medicinal Preparation (AREA)
Abstract
A transdermal Nitexinong patch contains medicine-carrying layer, back lining layer and anti-sticking layer, in which the medicine-carrying layer is composed of Nitexinong as active component, penetration promoter and pressure-sensitive adhesive matrix. The weight percentage content of the nitisinone in the drug-carrying layer is 4 percent to 7 percent. The weight percentage content of the penetration enhancer in the drug-loaded layer is 1.5% -2.5%, the penetration enhancer is lauryl alcohol and N-alkyl benzisothiazolone, and the lauryl alcohol and the N-alkyl benzisothiazolone are 1: 0.2 to 0.5. The pressure sensitive adhesive matrix is a hot melt pressure sensitive adhesive matrix.
Description
Technical Field
The invention relates to a transdermal drug delivery preparation, in particular to a transdermal patch taking nitisinone.
Background
Nitisinone (CAS:104206-65-7, Nitisinone), a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD). Nitisinone is the first choice drug for treating type I tyrosinemia (HT-1), which is an autosomal recessive hereditary clinical syndrome with tyrosine metabolism abnormality, severe liver injury, and renal tubule defect caused by fumarylacetoacetate hydrolase deficiency. Type I tyrosinemia (HT-1) is a disease caused by accumulation of tyrosine and its metabolites, such as succinylacetone, 4-hydroxyphenyllactic acid and 4-hydroxyphenylpyruvic acid, due to FAH gene mutation, which results in defect of the end enzyme, fumarylacetoacetate hydrolase, in the tyrosine metabolic process. HT-1 is treated by controlling diseases through diet, medicine or liver transplantation, reducing blood tyrosine and its metabolite level, and relieving tyrosine and its metabolite damage to organism. Nitisinone started to apply clinical treatment in 1992, is the only effective drug for treating HT-1 at present, and can prevent accumulation of maleylacetoacetic acid, fumarylacetoacetate and succinylacetone, a by-pass metabolite thereof, which have extremely high toxicity, by inhibiting normal metabolism of tyrosine in HT-1 patients, thereby relieving liver and kidney function damage, alleviating symptoms, obviously improving long-term prognosis, improving survival rate, and reducing incidence rate of hepatocellular carcinoma. The existing nitisinone is mainly in oral dosage forms, including capsules of 5mg and 10 mg. However, oral administration of drugs presents difficulties due to the onset of disease in many patients from a very low age. How to change the administration mode, the adoption of the percutaneous administration mode to improve the compliance becomes a problem which needs to be waited in the prior art.
Disclosure of Invention
In order to solve the technical problems, the invention adopts the technical scheme that:
the transdermal nitisinone patch is characterized by comprising a drug-loaded layer, a back lining layer and an anti-sticking layer, wherein the drug-loaded layer consists of nitisinone serving as an active ingredient, a penetration enhancer and a pressure-sensitive adhesive matrix.
The transdermal patch of nitisinone is characterized in that the weight percentage content of the nitisinone in the drug-loaded layer is 4-7%, and the preferential content is 5%.
The transdermal nitisinone patch is characterized in that the content of a penetration enhancer in the drug-loaded layer is 1.5-2.5 wt%, the penetration enhancer is preferably lauryl alcohol and N-N-alkyl benzisothiazolinone, and the ratio of the lauryl alcohol to the N-N-alkyl benzisothiazolinone is 1: 0.2 to 0.5. The lauryl alcohol and the N-alkylbenzisothiazolinone are 1: 0.4..
The nitisinone transdermal patch is characterized in that the pressure-sensitive adhesive matrix is a hot-melt pressure-sensitive adhesive matrix.
The preparation method of the nitisinone transdermal patch comprises the following steps:
1) mixing nitisinone, lauryl alcohol, N-N-alkyl benzisothiazolinone and hot melt pressure sensitive adhesive matrix uniformly, coating on the anti-sticking layer, drying at 65-85 deg.C, compounding with the back lining layer, and cutting into patch.
The transdermal patch of nitisinone provided by the invention can be used for transdermal administration of nitisinone by optimizing an auxiliary material formula. The transdermal drug delivery of the nitisinone can be realized, so that the transdermal drug delivery can be used for certain patient groups with poor compliance of taking oral preparations.
Detailed Description
All percentages in the examples are by weight
Example 1
4 percent of nitisinone
Lauryl alcohol 1%
N-N-alkyl benzisothiazolinone 0.5%
The rest of the hot-melt pressure-sensitive adhesive matrix is prepared by the following method
Mixing nitisinone, lauryl alcohol, N-N-alkyl benzisothiazolinone and hot melt pressure sensitive adhesive matrix uniformly, coating on the anti-sticking layer, drying at 65-85 deg.C, compounding with the back lining layer, and cutting into patch.
Example 2
Nitisinone 7%
Lauryl alcohol 2%
N-N-alkyl benzisothiazolinone 0.4%
The rest of the hot-melt pressure-sensitive adhesive matrix is prepared by the following method
Mixing nitisinone, lauryl alcohol, N-N-alkyl benzisothiazolinone and hot melt pressure sensitive adhesive matrix uniformly, coating on the anti-sticking layer, drying at 65-85 deg.C, compounding with the back lining layer, and cutting into patch.
Example 3
Nitisinone 5%
Lauryl alcohol 1.5%
N-N-alkyl benzisothiazolinone 0.6%
The rest hot-melt pressure-sensitive adhesive matrix is prepared by the following method
Mixing nitisinone, lauryl alcohol, N-N-alkyl benzisothiazolinone and hot melt pressure sensitive adhesive matrix uniformly, coating on the anti-sticking layer, drying at 65-85 deg.C, compounding with the back lining layer, and cutting into patch.
Example 4
Nitisinone 5%
Lauryl alcohol 1.9%
N-N-alkyl benzisothiazolinone 0.6%
The rest hot-melt pressure-sensitive adhesive matrix is prepared by the following method
Mixing nitisinone, lauryl alcohol, N-N-alkylbenzisothiazolinone and hot melt pressure sensitive adhesive matrix uniformly, coating on the anti-sticking layer, drying at 65-85 deg.C, compounding with the back lining layer, and cutting into patch.
By examining the patches of examples 1-4, it is known that the content uniformity, release rate, initial adhesion, holding adhesion, and peel strength all meet the relevant specifications in the patch in appendix IV of the second part of the chinese pharmacopoeia 2015 edition.
Pharmacological example 1 in vitro transdermal penetration experiment of a nitisinone transdermal patch.
The vertical diffusion cell is adopted, and the effective diffusion area is 2.8cm2The skin used was a depilated pig ear skin, approximately 600 μm thick. The patch is attached to one side of horny layer of ear skin of unhaired pig, and is placed between a diffusion pool and a receiving pool, wherein the horny layer faces the diffusion pool, and the dermis layer faces the receiving pool. The receiving pool is 6.5mL, filled with pH7.4PBS and removed of bubbles, and placed in a circulating water bath magnetic stirring pool, the rotating speed of magnetons is set to 300r/min, and the temperature of the water bath is 37 ℃. 1mL of samples were taken at 2h, 4h, 6h, 8h, 10h, 12h, 14h and 24h after initiation of transdermal penetration, fresh receiving solution was immediately replenished after sampling, the samples were filtered through a 0.45 μm microporous filter membrane, and the concentration of nitisinone was measured by high performance liquid chromatography, and the transdermal permeation rate and the cumulative permeation amount were calculated, and the results were as shown in the following table (means. + -. SD, n ═ 3)
Group of | Transdermal penetration Rate (μ g).cm-2.h-1) | Cumulative amount of penetration (. mu.g).cm-2) |
Example 1 | 0.62±0.09 | 7.35±0.45 |
Example 2 | 0.72±0.08 | 8.64±0.31 |
Example 3 | 0.93±0.09 | 11.21±0.39 |
Example 4 | 0.85±0.11 | 9.96±0.60 |
Experimental results show that the transdermal patch provided by the invention can realize in-vitro transdermal drug delivery of nitisinone under the condition that a pressure-sensitive adhesive matrix and a penetration enhancer are optimized.
Claims (6)
1. The transdermal nitisinone plaster features that the transdermal nitisinone plaster includes medicine carrying layer, back lining layer and anti-sticking layer, and the medicine carrying layer consists of nitisinone as active component, permeation promoter and pressure sensitive adhesive matrix.
2. The transdermal nitisinone patch according to claim 1, wherein the content of the nitisinone in the drug-carrying layer is 4-7% by weight.
3. The transdermal nitisinone patch according to claim 2, wherein the content of nitisinone in the drug-loaded layer is 5% by weight.
4. The transdermal nitisinone patch according to any one of claims 1 to 3, wherein the content of penetration enhancer in the drug-loaded layer is 1.5 to 2.5% by weight, the penetration enhancer is lauryl alcohol and N-alkylbenzisothiazolinone, and the lauryl alcohol and N-alkylbenzisothiazolinone are 1: 0.2 to 0.5.
5. The transdermal nitisinone patch according to claim 4, wherein the lauryl alcohol and the N-alkylbenzisothiazolinone are 1: 0.4.
6. the transdermal nitisinone patch according to any one of claims 1 to 5, wherein the pressure sensitive adhesive matrix is a hot melt pressure sensitive adhesive matrix.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210417121.0A CN114732802A (en) | 2022-04-20 | 2022-04-20 | Netixinong transdermal patch |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210417121.0A CN114732802A (en) | 2022-04-20 | 2022-04-20 | Netixinong transdermal patch |
Publications (1)
Publication Number | Publication Date |
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CN114732802A true CN114732802A (en) | 2022-07-12 |
Family
ID=82284181
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210417121.0A Pending CN114732802A (en) | 2022-04-20 | 2022-04-20 | Netixinong transdermal patch |
Country Status (1)
Country | Link |
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CN (1) | CN114732802A (en) |
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2022
- 2022-04-20 CN CN202210417121.0A patent/CN114732802A/en active Pending
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