WO2004071484A1 - Liniment de chlorhydrate de levamisole - Google Patents

Liniment de chlorhydrate de levamisole Download PDF

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Publication number
WO2004071484A1
WO2004071484A1 PCT/CN2004/000117 CN2004000117W WO2004071484A1 WO 2004071484 A1 WO2004071484 A1 WO 2004071484A1 CN 2004000117 W CN2004000117 W CN 2004000117W WO 2004071484 A1 WO2004071484 A1 WO 2004071484A1
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WO
WIPO (PCT)
Prior art keywords
levamisole hydrochloride
liniment
volume
levamisole
skin
Prior art date
Application number
PCT/CN2004/000117
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English (en)
Chinese (zh)
Inventor
Qinwen Zhu
Kaisu Zhu
Original Assignee
Qinwen Zhu
Kaisu Zhu
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Filing date
Publication date
Application filed by Qinwen Zhu, Kaisu Zhu filed Critical Qinwen Zhu
Publication of WO2004071484A1 publication Critical patent/WO2004071484A1/fr

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Classifications

    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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

Definitions

  • the present invention relates to the field of medicine, and more particularly, to levamisole hydrochloride liniment. Background technique
  • levamisole hydrochloride The pharmacological basis of levamisole hydrochloride is that it has no effect on the body with normal immune function, but only has a significant enhancement effect on cases with low immune function, so that it returns to normal. It mainly acts on T lymphocytes, induces early T cells to differentiate and mature into functional T cells, and restores dysfunctional T cells to normal. At the same time, it can enhance the chemotactic and phagocytosis of monocytes, and activate macrophages and granulocytes. Cell migration inhibitory factor induces endogenous interferon, which results in improved immune function and antiviral efficacy.
  • benzimidazole a metabolite of levamisole hydrochloride in the body, has stronger immunoregulatory effects than oligozole, in addition to having thymosin-like and regulating cyclic nucleotide functions, it also has a strong free radical scavenging effect.
  • Clinical application research shows that levamisole hydrochloride can significantly inhibit the replication of hepatitis B virus, clear the serum markers HBVDNA, and anti-HBclgM. It can improve the immunity and anti-cancer ability of cancer patients in adjuvant chemotherapy / radiotherapy for advanced cancer patients; Has a significant effect in the application of asthma patients.
  • the existing levamisole hydrochloride preparation products are only available as an oral tablet, and the oral side-effect rate is generally about 30%, mainly due to nausea, vomiting, gastrointestinal discomfort, gastrointestinal reactions such as abdominal pain, dizziness, headache, etc. . Therefore, long-term medication cannot be adhered to, which affects the efficacy.
  • Some people have tried to make levamisole hydrochloride injections, but many cases of animal (dog) death occurred in the animal experiment. Therefore, there is an urgent need for a levamisole hydrochloride formulation product that is safe, has no side effects, and is easy to use.
  • the object of the present invention is to provide a levamisole hydrochloride preparation product which can fully ensure safety, has no side reactions, and is convenient to use.
  • the present inventors conducted intensive research in order to achieve the above-mentioned object, and found that, as long as the levamisole hydrochloride is dissolved in a certain proportion of isopropyl alcohol, propylene glycol, nitrogen ketone, and distilled water, In a mixed solvent, the obtained levamisole hydrochloride solution can be used as a tincture for administration through the skin, and this levamisole hydrochloride tincture can ensure safety, quick effect, no side effects, convenient use, and low cost. A research result, thus completing the present invention.
  • a levamisole hydrochloride saliva characterized in that the tincture is dissolved by levamisole hydrochloride at a final concentration of 20-200mg / ml in 10-40 vol% isopropanol and 5-30 vol% propylene glycol 0.5-5% by volume of Azone, and the remainder less than 100% by volume are composed of a mixed solvent composed of pure water.
  • the technical solution of the present invention is described in detail below.
  • the final concentration mentioned in the above technical solution (1) refers to the concentration when formulated into a finished product of levamisole hydrochloride liniment.
  • the amount of levamisole hydrochloride should be in the range of 20-200 mg.
  • the normal dose is 500 mg each time, if the concentration of levamisole hydrochloride is lower than
  • the concentration of levamisole hydrochloride was set to 20 mg / ml.
  • the concentration of levamisole hydrochloride is more than 200mg / ml, the amount of liquid medicine to be applied each time is less than 2.5ml, so the area of the skin that can be touched is too small, which affects the skin's effect on the active ingredients. Absorption rate. Therefore, the upper limit of the concentration of levamisole hydrochloride was set to 200 mg / ml.
  • Azone also known as Laurocapi'amum
  • Laurocapi'amum is a highly effective and non-toxic enhancer for transdermal absorption, which can change the structure of the stratum corneum and promote drug absorption. If the content of Azone is less than 0.5% by volume, the effect of promoting the transdermal absorption of the drug is too small. In addition, if the content of Azone is greater than 5% by volume, a certain degree of irritation may be generated. Therefore, the content range of Azone is selected from 0.5 to 5% by volume.
  • Isopropanol mainly promotes the transdermal absorption of levamisole hydrochloride. If the content of isopropanol is less than 10% by volume, its effect is too small. On the other hand, if its content is greater than 40% by volume is economically disadvantageous, so the content range is selected to be 10-40% by volume.
  • Propylene glycol has two hydroxyl groups, so its boiling point (188.2 ° C) is significantly higher than that of isopropanol (boiling point 82.5 ° C), and its volatilization rate is also slower than that of isopropanol. Therefore, it can prolong the use of Azone and isopropanol in the skin's keratin.
  • propylene glycol has a protective effect on the skin, so it is widely used in cosmetics. If the content of propylene glycol is less than 5 vol ° / o, its effect is too small. On the contrary, if its content is more than 30% by volume, it will cause an increase in cost, and also cause the solvent to volatilize too slowly, making the patient feel inconvenient to use. Therefore, the content range of propylene glycol is selected to be 5-30% by volume.
  • the indications of the levamisole hydrochloride tincture of the present invention are basically the same as those of the levamisole hydrochloride tablets, but there are no side effects such as those seen when taking tablets.
  • This product can be absorbed through the skin to achieve the purpose of systemic immunotherapy. And this product is easy to use. When you use the medicine, you only need to open the seal of the medicine bottle, squeeze the liquid medicine gently, and apply it to your legs or forearms while dripping.
  • the levamisole hydrochloride tincture of the present invention has the following beneficial effects:
  • the frequency of medication is much less than that of oral medication
  • the purpose of this experimental example is to determine the chemical composition distribution ratio that allows levamisole hydrochloride as an active ingredient to penetrate the skin faster.
  • rat skin was used instead of human skin.
  • levamisole hydrochloride was dissolved in an appropriate amount of water in the proportion shown in Table 1 to obtain an aqueous levamisole hydrochloride solution.
  • acetone is dissolved in propylene glycol and isopropanol, and the two solutions are mixed and hooked, and then filtered, and water is added to the filtrate to make up
  • the 751 ultraviolet spectrophotometer was used to measure the absorbance of the solution at a wavelength of 215 Inm to quantitatively analyze the concentration of levamisole hydrochloride.
  • the back of the mouse was decapitated with a depilatory agent and sacrificed.
  • the back was peeled without skin to remove subcutaneous fat, washed with normal saline, and then wrapped with a sterile normal saline gauze.
  • Vaseline gauze was stored and stored for 4 days.
  • the experimental device uses a modified Franz diffusion chamber, which consists of two cup-shaped glass components facing each other.
  • the isolated rat skin is sandwiched in the middle to form two upper and lower chambers (the skin keratin is facing the supply chamber), the upper chamber is the supply chamber, and the lower chamber is the receiving chamber; an upwardly inclined pipe is connected to the receiving chamber side for sampling, Replenish pH buffer or eliminate bubbles.
  • a magnetic rod stirrer is set at the bottom of the receiving chamber.
  • the upper and lower parts of the device are tightened with rubber bands, and the supply liquid (ie, sample) preheated to 37 ° C is added to the supply chamber, and the PBS solution pH7.3 preheated to 37 ° C is added to the receiving chamber; adjust the electromagnetic stirring speed.
  • the supply liquid ie, sample
  • the PBS solution pH7.3 preheated to 37 ° C is added to the receiving chamber; adjust the electromagnetic stirring speed.
  • the sample to be measured was measured at 215 ⁇ lnm on a 751 UV spectrophotometer with water as the blank, and the absorbance (A1) was measured; 6 mice were used for each prescription The skins were made 6 times in total, and each prescription matrix was made in the same way as above.
  • the formulation matrix (vehicle solution) containing no levamisole hydrochloride liniment in the release pool was made from 3 mouse skins a total of 3 times, and the absorbance (A2) was measured as a blank control.
  • A1-A2 AS combined with the standard curve, the total receiving solution concentration and the cumulative release rate at each time were calculated.
  • the cumulative frontal release rate (%) of levamisole hydrochloride obtained in each experiment and its standard deviation are shown in Table 2.
  • This experimental example is to study the effect of levamisole hydrochloride liniment of the present invention on the formation of hemolysin. Forty male mice were used, and the mice weighed 20 ⁇ 2 g. Randomly divided into 5 groups, 8 in each group. Each mouse was injected intraperitoneally with 0.2 ml of 3: 5 diluted sheep red blood cells to induce a hemolytic response in mice. On the day of sensitization, the drug was administered through the skin, that is, the levamisole hydrochloride tincture 0.625 at a concentration of 100 mg / ml (prescription 2 in Table 1 and the same below) was applied to the depilated skin (2 X 2 cm) of the mice.
  • the tincture of the present invention refers to prescription 2 in Table 1, in which the content of levamisole hydrochloride is 100 mg / ml, the same applies hereinafter.
  • the present invention levamisole hydrochloride liniment 0.625-2.5ml / kg (6 2. 5 _ 2 50mg / kg) significantly increased the formation of hemolysin, CH50 increased value, in particular When the dose of levamisole hydrochloride was 250 mg / kg, the effect was much better than that of Tremella polysaccharide as a positive control.
  • the results indicate that topical skin administration of levamisole hydrochloride liniment has the effect of humoral immune function of the body.
  • This experimental example is to study the effect of the levamisole hydrochloride liniment of the present invention on the mouse reticuloendothelial system.
  • mice 50 ICR mice, half male and half male, weighing 20 ⁇ 2 g, were randomly divided into 5 groups of 10 mice each. Respectively, the back skin depilation (2 2cm) coated liniment levamisole hydrochloride 0.65, 1.25, 2.5ml / kg, vehicle 10ml / k g As a control, Tremella polysaccharide 10ml / kg (lml Tremella polysaccharide containing 20ml) orally as a positive Sex control. It was administered once a day for 4 days.
  • the levamisole hydrochloride liniment of the present invention can significantly improve the clearance ability of carbon particles injected by mice, and the phagocytosis index (K) The values and phagocytosis coefficient ( ⁇ ) increased significantly.
  • the dosage of levamisole hydrochloride is 250mg / kg, its effect is obviously better than Tremella polysaccharide. This fact indicates that topical skin administration of levamisole hydrochloride liniment has a significant enhancement effect on the function of the reticuloendothelial system in mice.
  • This experimental example is to study the effect of levamisole hydrochloride of the present invention on the weight of immune organs in mice.
  • Fifty male ICR mice were used and the weight of the mice was 13 ⁇ lg. They were randomly divided into 5 groups of 10 mice each.
  • tremella polysaccharide 10ml / kg (1ml containing tremella polysaccharide 20mg) was taken orally as a positive control.
  • This experimental example is to study the prevention and treatment effect of levamisole hydrochloride liniment of the present invention on experimental allergic meningitis of guinea pigs. Forty male white guinea pigs were used. Each guinea pig weighed 350 ⁇ 50 g and was randomly divided into 5 groups of 8 guinea pigs. The first group was given a vehicle at a dose of 1.5 ml / kg every other day (qod).
  • Groups 2, 3 and 4 were given levamisole hydrochloride liniment at a concentration of 100 mg / ml (prescription 2 in Table 1), each dose was 1.5 ml / kg (150 mg / kg), and the administration time was once a day (qd ), Once every other day (qod) and once every three days (q3d).
  • the fifth group was given fluocinolone ointment, each dose was 1.5 mg / kg, once a day (qd).
  • Each group was administered with back skin (pre-hair removal with 8% sodium sulfide solution, area 4 X 4cm). After one week of administration, guinea pigs were intradermally injected with an antigen-adjuvant emulsion of 0.05ml each.
  • Sensitization intensified sensitization on the 9th day after sensitization, discontinued the drug on the 6th day after the sensitization, and continued to observe for 2 days, record the performance and death of the animals, and take part of the brain and spinal cord for pathological observation.
  • the results obtained are shown in Table 6.
  • the responses of dead animals include loss of appetite, weight loss, dragging of hind limbs, paroxysmal convulsions before the death, angled arch reversal, and incontinence. Examination of cerebral spinal cord pathological sections of dead animals in each group showed cerebrospinal membrane inflammation without significant differences.
  • the topical skin administration of the levamisole hydrochloride liniment of the present invention has a better prevention and treatment effect on experimental allergic encephalomyelitis in guinea pigs, and the mortality rate is significantly reduced. Larger doses work better.
  • the beneficial effects of the levamisole hydrochloride liniment of the present invention are: there are no side effects when used; it will not cause the patient to feel the pain when it is taken orally; the frequency of medication is much less than that of oral medicine; the use is convenient; It can reduce the financial burden on patients; the production process is simple and the number of procedures is small. Therefore, it has good industrial applicability.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un liniment contenant du chlorhydrate de lévamisole. Ce liniment comprend entre 20 et 200 mg/ml (concentration finale) de chlorhydrate de lévamisole comme agent actif, ainsi qu'un solvant mixte renfermant entre 10 et 40 % (v/v) d'alcool isopropylique, entre 5 et 30 % (v/v) de propylène glycol, entre 0,5 et 5 % (v/v) d'ozone et de l'eau purifiée.
PCT/CN2004/000117 2003-02-14 2004-02-12 Liniment de chlorhydrate de levamisole WO2004071484A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN03102696.6 2003-02-14
CNB031026966A CN1197573C (zh) 2003-02-14 2003-02-14 盐酸左旋咪唑搽剂

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WO2004071484A1 true WO2004071484A1 (fr) 2004-08-26

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WO (1) WO2004071484A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20020097454A (ko) 2001-06-21 2002-12-31 엘지전자 주식회사 멀티채널 스트림 기록장치 및 방법과, 그에 따른 기록매체
KR100598285B1 (ko) 2001-06-21 2006-07-07 엘지전자 주식회사 멀티채널 스트림 기록장치 및 방법과, 그에 따른 기록매체
WO2004042723A1 (fr) 2002-11-08 2004-05-21 Lg Electronics Inc. Procede et appareil permettant d'enregistrer un flux a composants multiples et un support d'enregistrement a haute densite comprenant un flux a composants multiples enregistre et procede et appareil de reproduction dudit support d'enregistrement
US7664372B2 (en) 2002-11-20 2010-02-16 Lg Electronics Inc. Recording medium having data structure for managing reproduction of multiple component data recorded thereon and recording and reproducing methods and apparatuses
US7224664B2 (en) 2003-03-25 2007-05-29 Lg Electronics Inc. Recording medium having data structure for managing reproduction of data streams recorded thereon and recording and reproducing methods and apparatuses

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1099616A (zh) * 1994-04-04 1995-03-08 朱钦文 新型的左旋咪唑搽剂

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1099616A (zh) * 1994-04-04 1995-03-08 朱钦文 新型的左旋咪唑搽剂

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FUJIAN MEDICAL JOURNAL, vol. 12, no. 1, 1990 *
ZHU QINWEN, CHINESE JOURNAL OF ZOONOSES, vol. 3, no. 4, 1987, pages 2 *

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CN1197573C (zh) 2005-04-20
CN1430958A (zh) 2003-07-23

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