WO2008022535A1

WO2008022535A1 - A pharmaceutical composition for treating brain glioma, its process and pharmaceutical preparation

Info

Publication number: WO2008022535A1
Application number: PCT/CN2007/002389
Authority: WO
Inventors: Jianming Chen; Zhengliang Ye; Guangming Zhang; Jiuhe Peng
Original assignee: Tian Jin Tasly Group Co., Ltd.
Priority date: 2006-08-09
Filing date: 2007-08-09
Publication date: 2008-02-28

Abstract

A pharmaceutical composition for treating brain glioma, comprising temozolomide, borneol and/or menthol, wherein the weight rate of temozolomide: borneol and/or menthol is 1-50:2-100. The present invention also provides pharmaceutical preparation containing the above composition, and the process for the composition. The present pharmaceutical composition is very simple, and it has good curative effect and lower side effect, and the dose is also low.

Description

TECHNICAL FIELD The present invention relates to the field of medical technology, and in particular to a composition for treating glioma, a preparation method thereof and a preparation. BACKGROUND ART A brain tumor disease refers to a tumor that occurs in the brain, and can be classified into a primary brain tumor and a metastatic tumor derived from a lung tumor or the like according to the source of the lesion. The biggest difference between brain tumors and tumors in other parts is that brain tumors are surrounded by skulls. It is for this reason that doctors caution patients not to be taken lightly if they have brain tumor disease, even a benign brain tumor can be life-threatening. The brain is the "command" of the human body. If a tumor is produced in the brain, it will oppress the brain, causing damage to the function of the brain and causing systemic diseases. Because the brain is also the center of thinking, personality and emotion, brain tumors bring not only It is the above-mentioned physical hazard. Due to the long-term suffering of the disease, the patient is also severely devastated by the mental will. Many patients have a suicidal idea, so the brain tumor is often called "mental cancer." It has been found that although brain tumors are not the first disease of morbidity and mortality, the incidence rate among children and adolescents ranks second, second only to blood cancer. More than 60% of adult primary brain tumors are gliomas and malignant melanoma. This is a very dangerous malignant tumor with high morbidity and high mortality. It is calculated from the initial diagnosis and has a survival of only 9-12 months. Although patients undergo surgery, radiotherapy, and chemotherapy, brain tumor recurrence occurs almost without exception. In the past 20 years, the treatment of glioma has not progressed significantly. Gliomas and malignant melanoma are quite difficult to treat, and the mortality is high, it is difficult to control, the operation is not easy to remove, and the recurrence rate is high. At present, chemotherapy has limited effect on glioma, mainly because: (1) tumors are not sensitive to drugs; (2) tumor drugs have low effective concentrations, and adverse effects of drugs on the whole system make chemotherapy difficult to maintain; The most important is the presence of the blood-brain barrier (BBB), a regulatory interface between capillaries and nerve tissue in the brain and spinal cord. The optimal glioma chemotherapy drug should pass the blood-brain barrier smoothly, is not toxic to the central nervous system, maintains an effective concentration in the blood and cerebrospinal fluid for a long time, and the molecular weight of the drug is relatively small. Currently, conventional treatments for clinical gliomas are surgery, radiation, and chemotherapy. There are few drugs for glioma chemotherapy. The existing chemotherapeutic drugs are nitrosoureas such as nitrosourea alkylating agent carmustine (BCNU) and nitrosourea (CCNU), or PVC solution ( Methyl benzamidine + vincristine + CCNU), but its shortcomings are short plasma half-life; large side effects, delayed and cumulative myelosuppression and pulmonary toxicity; high toxicity; prone to drug resistance, after initial treatment relapse Treatment again will not work. Malignant melanoma is also a more common cancer with a high degree of malignancy. The conventional chemotherapy drugs are BCNU and CCNU. However, these drugs also have problems such as poor efficacy, large side effects, and resistance to drug resistance. Temozolomide was produced by Schering-Plough and first launched in September 1999. Through a franchise transfer agreement with the British CRC Technology, the company acquired the exclusive right to sell temozolomide worldwide. It is a new anticancer drug for the treatment of glioma and malignant melanoma. It is the first compound of imidazotetrazine. This oral cytotoxic deuteration agent can be long due to its low toxicity and good tolerance. Time medication has improved long-term efficacy, and the patient's physical and mental state has been significantly improved, improving the quality of life of patients, and taking an important step in the treatment of glioblastoma. After conventional chemotherapy (BCNU, CCNU) develops drug resistance, temozolomide is still effective, and these two drugs are not only cross-resistant and synergistic. It is better to keep the patient's condition from developing and prolonging the survival time than the standard treatment of procarbazine. Therefore, temozolomide is currently the relatively best drug for the treatment of gliomas and malignant melanoma. In the 2005 Clinical Research Development Report published by the American Society of Clinical Oncology (ASCO), it was clearly stated that temozolomide inhibited the proliferation and spread of cancer cells. Temozolomide combined with radiotherapy prolonged the lifespan of some patients with malignant glioma, and was approved by the US FDA. Recommended by the Oncology Drug Advisory Committee. Temozolomide does not directly act in vivo, and at physiological pH it is rapidly converted to the active compound MTIC [5-(3-methyltriazene-1-)imidazole-4-amide] via a non-enzymatic pathway. It is rapidly absorbed after oral administration and has nearly 100% bioavailability and broad-spectrum anti-tumor activity. The main side effects are mild nausea, vomiting, fatigue, constipation and mild myelosuppression. Other common adverse reactions are fatigue, headache, dizziness, shortness of breath, hair loss, anemia, fever, and decreased immunity. Although oral temozolomide is not metabolized by the liver and widely distributed throughout the body, and has such high bioavailability, how to make it pass through the blood-brain barrier to exert a definite therapeutic effect is an urgent need to be solved. problem. Furthermore, how to alleviate or even eliminate the patient's adverse reactions during treatment is also a problem that cannot be ignored. Borneol is a natural crystalline compound precipitated from the resin of the dipterocephalic plant Dipterocarp. The herb is called dipterocarp, which has been used for thousands of years. It is mainly produced in Sumatra and other places in Indonesia. Due to the tight production resources, artificial synthetic products such as camphor and turpentine are used instead. The main component of natural borneol is bomeol, and the synthetic borneol is a racemate containing a large amount of Isoborneol. The biggest features of borneol are two: one is "aromatic walking", and the other is "extracting medicine". These two characteristics make the borneol get the reputation of "encephalopathy angel". "Aromatic walking" means that borneol has a strong divergence effect, called "walking sputum". The clinical response of this "walking" effect is rapid and ubiquitous. "Applicator up" means that borneol can not only pass through the blood-brain barrier, but also increase the permeability of the blood-brain barrier, and promote other drugs to enter the brain through the blood-brain barrier. Modern research has found that the main component of borneol is the bicyclic monoterpene decane derivative borneol, which is a racemic mixture of borneol.

"Materia Medica" believes that borneol is "weak and weak, and the ambassador is effective." In the prescription, the borneol is made into "medicine lead", and the active ingredient is Leading to the lesion, modern pharmacological research is called "targeting". The role of borneol is that it not only can resist oxidation, but also can improve the permeability of the blood-brain barrier, allowing the "master drug" to fully enter the brain to play a therapeutic role. In addition, mice were tested by hot plate method and found that the use of borneol can prolong the lameness time, indicating that the borneol has obvious analgesic and sedative effects. In this way, in combination with the drug, it can alleviate the adverse reactions such as headache, fatigue, dizziness, fatigue and fever in patients after oral temozolomide. Menthol is a colorless crystal precipitated from the lip of the Labiatae at a slightly lower temperature and is a crystal of menthol. Like borneol, menthol, which is also an aromatic drug, also has the effect of "fragrance opening and appending medicine". The ancient Chinese "Shang Qing San" (see "Prescription of the Royal Hospital") applies to brain tumors, and the mint leaves in the group play an immeasurable role. Recently, researchers at the National Stanford University in the United Kingdom found that mint can destroy tumor cells, which is probably the role of menthol. The traditional way of treating cancer is to destroy the tumor cells, and the mint extract sets the target on the blood vessels that supply nutrients to the tumor cells, so that the tumor cells cannot proliferate due to lack of oxygen and nutrients. Moreover, the side effects of such treatments will be Relatively low. Modern medicine has confirmed that menthol not only promotes the absorption of drugs, but also has its own specific effects in relieving neuropathic vomiting. Pharmacology shows: Oral small dose of peppermint mainly through the excitation of the central nervous system, the skin vasodilatation, promote the secretion of sweat glands to increase heat dissipation, have a sweating effect, increase the dose can stimulate the spinal cord to make the reflex can paralyze, and can stop vomiting . In this way, the combination of menthol and temozolomide not only highlights the anti-tumor, but also effectively counteracts the adverse reactions such as nausea and vomiting caused by temozolomide. Mint also shows positive effects in the digestive system and respiratory system as well as a unique calming and soothing effect, which relieves the patient of other common adverse reactions such as fatigue, fatigue, headache, dizziness, shortness of breath, fever, constipation and the like. SUMMARY OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition for treating gliomas which is simple in prescription, small in dosage, good in efficacy, and small in side effects. The object of the present invention is achieved by the following technical solutions: The present invention provides a pharmaceutical composition for treating glioma, including temozolomide and borneol and/or menthol. The pharmaceutical composition of the present invention, wherein the weight ratio of temozolomide: borneol and/or menthol is from 1 to 50: 2 to 100, preferably from 20 to 40: 32 to 100. The pharmaceutical composition of the present invention, wherein the borneol and/or menthol are preferably made into borneol and/or menthol cured, and the borneol and/or menthol cured means embedding borneol and/or menthol, Inclusion, embedding, etc. exist in solid excipients, It is brought to a non-volatile solid form. It may be, for example, a solid dispersion of borneol and/or menthol, a cyclodextrin inclusion compound of borneol and/or menthol, microspheres (capsules) of borneol and/or menthol, and the like. The solid dispersion of borneol and/or menthol according to the invention consists of borneol and/or menthol and a pharmaceutically acceptable carrier, wherein the weight ratio of borneol and/or menthol to pharmaceutically acceptable carrier is 1 : 1~20. The pharmaceutically acceptable carrier refers to a carrier that is pharmaceutically suitable for making a solid dispersion, including but not limited to conventional or conventional carriers in the art, preferably polyethylene glycol (PEG) having a molecular weight greater than 1000, Polyvinylpyrrolidone (PVP), poloxamer 188 (F68), ethylcellulose (EC), either alone or in combination. The polyethylene glycol (PEG) class having a molecular weight greater than 1000 includes, but is not limited to, PEG-1000, PEG-4000, PEG-6000, and the like. The polyvinylpyrrolidone (PVP) class includes, but is not limited to, PVPK15, PVPK30, PVPK90 and the like. The solid dispersion of borneol and/or menthol according to the present invention is prepared as follows: Weigh a prescribed amount of borneol and/or menthol and a carrier, dissolve together in an organic solvent, and volatilize and remove the organic solvent to obtain . The temperature at which the organic solvent is volatilized to remove is preferably 20 to 8 (TC. The organic solvent means an organic solvent suitable for pharmaceutically use, including but not limited to methanol, ethanol, acetone, isopropanol, n-butanol, dichloro Methane, chloroform, hexamethylene, hexamethylene, ethyl acetate, tetrahydrofuran, may be used singly or in combination. The borneol and/or menthol cyclodextrin inclusion compound of the present invention, wherein borneol and/or Or the weight ratio of menthol to cyclodextrin is 1:1 to 10. The blister and/or menthol cyclodextrin inclusion compound of the present invention can be prepared by: weighing a prescribed amount of borneol and/or Menthol, dissolved in an appropriate amount of aqueous organic solvent to obtain borneol and / or menthol solution; weigh cyclodextrin, prepare a saturated aqueous solution of cyclodextrin; mix the two by stirring or grinding to make the cyclodextrin The borneol and/or menthol are finely packed, dried under vacuum at low temperature to a solid, ground, washed, and dried to obtain a white loose inclusion powder. Specifically, the following two preparation methods can be used. Ready:

(1) Method: Weigh the prescribed amount of borneol and / or menthol, dissolved in an appropriate amount of aqueous organic solvent to obtain borneol and / Or menthol solution; weigh cyclodextrin, prepare a saturated aqueous solution of cyclodextrin; slowly add borneol and / or menthol solution to the saturated aqueous solution of cyclodextrin under stirring, continue to stir until The blister and/or menthol cyclodextrin inclusion complex, refrigerated, vacuum-dried to a solid at low temperature, ground, washed with ethyl acetate, and air-dried to obtain a white loose inclusion powder. The aqueous organic solution refers to an aqueous organic solvent suitable for pharmaceutically use, including but not limited to methanol, ethanol, acetone, isopropanol, n-butanol, ethyl acetate, tetrahydrofuran, which may be used alone or in combination; The stirring is preferably carried out at 20 to 80 ° C and the stirring rotation speed is preferably 100 to 2000 rpm. The stirring is preferably carried out for 10 to 200 minutes.

(2) Method: Weigh the prescribed amount of borneol and / or menthol, dissolved in an appropriate amount of aqueous organic solvent to obtain borneol and / or menthol solution; weigh cyclodextrin to prepare a saturated aqueous solution of cyclodextrin; The two are added to the grinder, thoroughly ground and mixed, and when the reactants form a viscous paste, they are vacuum dried to a solid at a low temperature, ground, washed, and dried to obtain a white loose inclusion powder. The aqueous organic solution refers to an aqueous organic solvent suitable for pharmaceutically use, including but not limited to methanol, ethanol, acetone, isopropanol, n-butanol, ethyl acetate, tetrahydrofuran, and may be used singly or in combination. The cyclodextrin refers to cyclodextrin and its derivatives, including but not limited to α-cyclodextrin, cyclodextrin, γ-cyclodextrin and its hydroxypropyl-β-cyclodextrin, 6-glucosyl group. -β-cyclodextrin and the like. The grinding and mixing is preferably carried out for 60 to 400 minutes. The borneol and/or menthol microspheres (capsules) according to the present invention are composed of borneol and/or menthol, capsules and emulsifiers in a weight ratio of 1:1 to 10: 0.01 to 5. The capsule material refers to a substance which is pharmaceutically suitable for forming microcapsules or microspheres, including but not limited to conventional or commonly used capsule materials, preferably acrylic resin, ethyl cellulose, which may be used alone or in combination. use. The acrylic resin includes, but is not limited to, commonly used marketed products Eudragit S, Eudragit RS, etc.; the emulsifier refers to a substance pharmaceutically suitable as an emulsifier, including but not limited to fatty acid sucrose ester, gelatin, arabic Glues can be used alone or in combination. The borneol and/or menthol microspheres (capsules) of the present invention are prepared as follows: Weigh a prescribed amount of borneol and/or menthol and capsule material, and dissolve the two together in an aqueous organic solvent to obtain an aqueous solution. Machine solution; weigh the emulsifier and prepare an aqueous emulsifier solution; under stirring, quickly pour the aqueous organic solution into the emulsifier aqueous solution, stir well until it becomes a microsphere (capsule), filter, and vacuum dry to a solid state at low temperature. Things, sifted, that's it. The concentration of the aqueous emulsifier solution is preferably 0.1 to 0,5 g/L. Among the stirring conditions described therein, the stirring speed is preferably from 50 to 2,000 rpm. The aqueous organic solvent means an aqueous organic solvent suitable for pharmaceutical use, including but not limited to ethanol, acetone, isopropanol, n-butanol, ethyl acetate, tetrahydrofuran, and may be used singly or in combination. The invention further relates to a formulation for treating glioma comprising temozolomide, borneol and/or menthol cured and a pharmaceutically acceptable carrier. The preparation may be formulated into any dosage form of pharmacy, such as pills, pills, capsules, granules, tablets, suspensions, injections, syrups, elixirs, powders, elixirs, topical medicinal solutions, Formulations such as sprays, suppositories, and the like, or other pharmaceutically acceptable dosage forms, preferably tablets and capsules. The above preparation of the pharmaceutical composition of the present invention can be produced according to a conventional or usual method in the art. The formulations of the invention are preferably tablets or capsules. The tablet or capsule comprises temozolomide, borneol and/or menthol cured, disintegrant, diluent, binder, and lubricant. The diluent used in the above formulation means a diluent which is pharmaceutically suitable for tableting or capsule preparation, including but not limited to conventional or conventional diluents in the art, preferably starch, sucrose, lactose, dextrin, microcrystals. Cellulose and calcium sulfate can be used singly or in combination. The disintegrant used in the above formulation means a disintegrant which is pharmaceutically suitable as a tablet or a capsule, and includes, but is not limited to, a disintegrator conventionally or commonly used in the art, preferably sodium carboxymethyl starch, hydroxypropyl The methylcellulose, the croscarmellose sodium, and the crospovidone may be used singly or in combination. The binder used in the above formulation means a binder which is pharmaceutically suitable for tableting or capsule preparation, including but not limited to a conventional or conventional binder in the art, preferably in a concentration of 2% to 10%. Starch pulp. The lubricant used in the above formulation means a lubricant which is pharmaceutically suitable for forming into a tablet or a capsule, and includes, but is not limited to, a lubricant conventionally or commonly used in the art, preferably magnesium stearate, silica gel, talc, Can be used alone or in combination. The tablet or capsule of the pharmaceutical composition of the present invention is as follows - the explanation is as follows:

Temozizizizil abandoned Qizi amine 0.5-25.0 parts by weight

Borneol and / or menthol cured product 1.0~50.0 parts by weight

7.0 to 95.5 parts by weight

0.5-8.0 parts by weight

1.0 to 5.0 parts by weight

The formulation of 0.5-5.0 parts by weight is preferably as follows _: temozolomide 5.0-10.0 parts by weight

Borneol and / or menthol cured product 8.0-25.0 parts by weight

55.0~83.2 parts by weight

1.0-3.0 weight ί

2.0-4.0 parts by weight

0.8 to 3.0 parts by weight The present invention also provides a method for preparing the above tablet or capsule, which is specifically as follows:

(1) Method: Weigh the prescribed amount of temozolomide, borneol and/or menthol solidified, mix, add diluent and disintegrant, mix well, add binder, granulate, add lubricant, mix , dry, whole, tableted or capsuled.

(2) Method: Weigh the prescribed amount of temozolomide, add diluent and disintegrant, mix well, add binder, granulate, add lubricant, mix, dry, and whole. The borneol and/or menthol solidified material is weighed, dissolved in an organic solvent to prepare a solution, and the solution is uniformly sprayed on the surface of the granules, naturally dried, tableted or encapsulated. In the above production method (2), the organic solvent for dissolving borneol and/or menthol cured product is ethanol. The present invention fully considers the unique properties of borneol, such as "adjuvant is active", "aromatic walking", "advancing medicine", and borneol and/or menthol against or alleviating the adverse reaction symptoms after taking temozolomide alone. A new compound for treating brain tumors, especially gliomas and malignant melanomas. Since the composition of the present invention is added with borneol and/or menthol, the amount of temozolomide is lowered, the therapeutic effect is improved, and the side effects are reduced. In addition, the preparation of the present invention is prepared by forming borneol and/or menthol into a cured product, so that the borneol and/or menthol in the molding preparation are not easily volatilized and sublimated during storage, and the drug content is stable and convenient. QC. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be further described in detail by way of specific examples, but the invention is not limited thereto. Description: The physicochemical properties of borneol and menthol are very similar, especially reflected in the preparation process of the present invention. The present invention has been found through specific preparation: It can be suitable for the menthol cured product or the preparation process of borneol cured product. Borneol and The preparation of the cured product of the menthol mixture, so in the specific embodiment of the borneol and/or menthol cured product, it is suitable for both the borneol cured product and the menthol cured product, or a cured product of a mixture of the two. Further, when the prepared borneol and/or menthol microcapsule morphology was observed by an electron microscope, it was found that the cured product obtained by the preparation process of the present invention was a microsphere and a microcapsule. In addition, the following examples also include embodiments of borneol and/or menthol microspheres (capsules). Preparation of borneol (or menthol) cured product Example 1 Preparation of borneol (or menthol) Solid dispersion Weighed borneol (or menthol) lOO.Og, PEG-4000 lOO.Og, PVPK30 200g, co-dissolved It is obtained by evaporating and removing ethanol at 80 ° C in ethanol. Example 2 Preparation of borneol (or menthol) solid dispersion Weighed borneol (or menthol) 50.0 g, PVPK30 120.0 g, co-dissolved in ethyl acetate, and evaporated at 40 ° C to remove ethyl acetate, ie Got it. Example 3 Preparation of borneol (or menthol) cyclodextrin inclusion compound 10.0 g of borneol (or menthol) was weighed and dissolved in an appropriate amount of acetone to obtain an acetone solution of borneol (or menthol); 60.0g of cyclodextrin was prepared as a saturated aqueous solution of a-cyclodextrin; the acetone solution of borneol (or menthol) was slowly added dropwise to the saturated aqueous solution of a-cyclodextrin at 25 rpm, 1000 rpm. The mixture was stirred for 80 minutes, refrigerated, and vacuum-dried to a solid. The mixture was triturated, washed with ethyl acetate, and dried to give a white powdery clathrate powder. Example 4 Preparation of borneol (or menthol) cyclodextrin inclusion compound 20.0 g of borneol (or menthol) was weighed and dissolved in an appropriate amount of n-butanol to obtain a solution of borneol (or menthol) in n-butanol; Weigh 200.0g of hydroxypropyl-β-cyclodextrin to prepare a saturated aqueous solution of hydroxypropyl-β-cyclodextrin; add the two to the mill, grind and mix for 300 minutes, and form a viscous paste. In the form of a vacuum, it was vacuum dried to a solid, crushed, washed with ethyl acetate, and dried to obtain a white loose inclusion compound powder. Example 5 Preparation of borneol (or menthol) microspheres (capsules) Weigh borneol (or menthol) 10.0 g, Eudragit S 2.0 g, ethyl cellulose 8.0 g, and dissolve the three together in an appropriate amount of ethanol to prepare An ethanol solution containing borneol (or menthol); weigh 2.0 g of fatty acid sucrose ester, and prepare 0.5 ml of a 0.5 g/L aqueous solution of fatty acid sucrose ester; at 1400 rpm, the above-mentioned borneol (or menthol) The solution is quickly poured into the above aqueous solution of the fatty acid sucrose ester, and thoroughly stirred to form borneol and/or menthol microspheres (capsules), filtered, vacuum dried to a solid at a low temperature, and sieved to obtain. Example 6 Preparation of borneol (or menthol) solid dispersion Weighed borneol (or menthol) 5.0 g, PEG-6000 lOO.Og, co-dissolved in a mixed solvent of acetone, n-butanol and cyclohexane, at 30 After volatilization and removal of the mixed solvent at ° C, it is obtained. Example 7 Preparation of borneol (or menthol) solid dispersion Weighed borneol (or menthol) 5.0 g, PEG-1000 40.0 g, PVPK90 20 g, co-dissolved in a mixed solvent of chloroform, methanol and cyclohexane. After volatilization at 50 ° C to remove the mixed solvent, it is obtained. Example 8 Preparation of borneol (or menthol) cyclodextrin inclusion compound 10.0 g of borneol (or menthol) was weighed and dissolved in a mixed solvent of methanol and ethyl acetate to obtain borneol (or menthol). a solution of 6-glucosyl-β-cyclodextrin 80.0 g, prepared as a saturated aqueous solution of 6-glucosyl-β-cyclodextrin; at 28 ° C, 1500 rev / min stirring speed, the above contains A solution of borneol (or menthol) is slowly added dropwise to a saturated aqueous solution of 6-glucosyl-β-cyclodextrin, stirred for 60 minutes, refrigerated, vacuum dried to a solid at low temperature, ground and washed with ethyl acetate. Drying, that is, a white loose inclusion powder. Example 9 Preparation of borneol (or menthol) cyclodextrin inclusion compound Weighing borneol (or menthol) 10.0 g was dissolved in a mixed solvent of an appropriate amount of ethanol, isopropanol and tetrahydrofuran to obtain borneol (or menthol). The solution was weighed and weighed 10.0 g of γ-cyclodextrin to prepare a saturated aqueous solution of γ-cyclodextrin; the two were added to a grinder, thoroughly ground and mixed for 120 minutes, and when the reactants formed a viscous paste, the low temperature vacuum The mixture was dried to a solid, triturated, washed with ethyl acetate and dried to give a white powdery powder. Example 10 Preparation of borneol (or menthol) microspheres (capsules) Weigh borneol (or menthol) 10.0 g, Eudragit S 100.0 g, and dissolve the two together in a mixed solvent of ethanol and acetone to obtain borneol. (or menthol) solution; weigh 2.0 g of fatty acid sucrose ester, 3.0 g of gum arabic, and make 50,000 ml of 0.1 g L emulsifier solution; at 1800 rpm, the above-mentioned borneol (or mint) The solution of the brain is quickly poured into the above aqueous emulsifier solution, stirred well for a certain period of time until it becomes a microsphere (capsule), filtered, vacuum dried to a solid at a low temperature, and sieved to obtain. Preparation Example of Compound Formula for Treatment of Gliomas Example 11 Preparation of Capsules 5.0 g of temozolomide and 25.0 g of borneol solid dispersion were weighed and mixed, and 62.5 g of microcrystalline cellulose and 2.0 g of sodium carboxymethyl starch were added. , mix well, add 2% starch slurry 4.0g, granulate, add 1.5g magnesium stearate, mix, dry, whole, package W capsules. Example 12 Preparation of tablets 10.0 g of temozolomide, 5.0 g of borneol microspheres (capsule), 15.0 g of menthol microspheres (sac) were weighed, and 50.0 _{g of} starch, 11.5 g of calcium sulfate, and hydroxypropylmethyl group were added. 2.5 g of cellulose, mix well, add 3% starch slurry 5.0g, granulate, add micro-silica gel l.Og, mix, dry, whole, and tablet. Example 13 Preparation of Tablets 8.0 g of temozolomide and 20.0 g of hydroxypropyl-β-cyclodextrin inclusion compound of menthol were weighed and mixed, and 43.0 g of microcrystalline cellulose, 21.8 g of sucrose, and crosslinked carboxymethyl group were added. Base cellulose sodium 3.0g, fully mixed hook, adding 2.5% starch slurry 3.0g, granulating, adding talc powder 1.2g, mixing, drying, sizing, tableting. Example 14 Preparation of capsules 12.0 g of temozolomide was weighed, 60.0 g of dextrin, 14.5 g of lactose, 5.0 g of crospovidone were added, and the mixture was thoroughly mixed. 1.0 g of starch slurry of 1.0% was added, granulated, and talcum powder was added. 2.5g, mix, dry, whole. Weigh 5.0g of menthol, dissolve it in an appropriate amount of ethanol to make a solution, spray this solution on the surface of the granules, dry it naturally at room temperature, and pack it. Example 15 Preparation of Tablets 6.0 g of temozolomide was weighed, and 50.0 g of starch, 5.0 g of sucrose, 6.5 g of lactose, 20.0 g of dextrin, and 3.5 g of sodium carboxymethyl starch were added, and the mixture was thoroughly mixed, and 2.0% of starch slurry was added. g, granulation, add 1.5g of magnesium stearate, mix, dry, whole. Weigh 2.0 g of borneol and 2.0 g of menthol, and dissolve the two together in an appropriate amount of ethanol to prepare a solution. The solution is evenly sprayed on the surface of the granules, and naturally dried at room temperature and compressed. Borneol extracts animal test of temozolomide through the blood-brain barrier. Preparation of the sample. Preparation of 1% sodium carboxymethylcellulose solution, then 1% sodium carboxymethylcellulose to prepare temozolomide suspension and temozolomide a mixed suspension with borneol, wherein the concentration of temozolomide in both suspensions is

2.2 mg/ml, in a mixed suspension of temozolomide and borneol, the concentration of borneol was 12.5 mg/ml. The above two solutions are respectively used as a temozolomide-free control sample containing no borneol and a temozolomide test sample containing borneol, and the prepared administration preparations, such as tablets and capsules, can also be ground with a 1% sodium carboxymethylcellulose solution. A mixed sample of temozolomide and borneol was prepared as a test sample, wherein the concentration of temozolomide was 2.2 mg/ml _; and 2.2 mg/ml of temozolomide suspension was used as a control sample.

P

BP Animals were tested in 20 Kunming mice, male and female, randomly divided into temozolomide-free control group without borneol and temozolomide test group containing borneol. The above prepared samples were administered to mice by gavage. All were 0.4ml/20g. After 1 hour of administration, 1.5ml of blood was taken from the eyelids. The mice were decapitated immediately after taking the blood. The whole brain was taken. After the surface vessels were peeled off, the blood was collected by filter paper and accurately weighed. Sample processing and determination of blood samples: 1.5 ml of blood sample was centrifuged at 12,000 rpm for 5 minutes, 200 μl of plasma was taken, 800 μl of methanol was added, vortexed, centrifuged, and 20 μl of the supernatant was taken. The blood was measured by HPLC. The concentration of temozolomide. Brain tissue: The whole brain was placed in a homogenizer, and the physiological saline was homogenized at a ratio of 5 ml/g, homogenized, placed in a centrifuge tube, vortexed for 3 minutes, and heated at 60 ° C for 1 hour, cooled to room temperature. Centrifuge for 10 minutes at 12,000 rpm, accurately extract 200 μl of the supernatant into a centrifuge tube, add 4 ml of ether, vortex for 10 minutes, centrifuge for 10 minutes, accurately pipette the supernatant 1.5 ml, and transfer to another tube. The nitrogen was blown dry, and the residue was dissolved in 100 μl of methanol, vortexed for 1 minute, centrifuged for 5 minutes, and 20 μl of the supernatant was taken, and the concentration of temozolomide in the brain tissue was measured by HPLC injection. Results 1. (Temozolomide concentration in brain tissue of the experimental group - temozolomide concentration in brain tissue of the control group) The concentration of temozolomide in the brain tissue of the control group was xl00% = 15.8%, which was significantly different by t test.

2. (Termozolam concentration in brain tissue of test group 替Temozolomide concentration in test group - Temozolomide concentration in brain of control group 血液 Temozolomide concentration in control group) ÷ (Temozolomide concentration in brain tissue of control group 血液 Temozolomide concentration in control group) Xl00%=20.2%, there is a significant difference after t test. The above results indicate that borneol can significantly increase temozolomide through the blood-brain barrier.

Claims

Claim

A pharmaceutical composition for treating glioma comprising temozolomide and borneol and/or menthol.

2. The pharmaceutical composition according to claim 1, wherein the weight ratio of temozolomide: borneol and/or menthol is 1 to 50: 2~

The pharmaceutical composition according to claim 1, wherein the weight ratio of temozolomide: borneol and/or menthol is 20 to 40: 32 to 100.

4. The pharmaceutical composition according to claim 1, wherein the borneol and/or menthol is borneol and/or menthol cured.

5. The pharmaceutical composition according to claim 4, wherein the borneol and/or menthol cured product is a solid dispersion of borneol and/or menthol, a blister and/or a cyclodextrin inclusion complex of menthol. Or borneol and/or menthol microspheres (capsules).

6. The pharmaceutical composition according to claim 5, wherein the solid dispersion of borneol and/or menthol consists of borneol and/or menthol and a pharmaceutically acceptable carrier, wherein borneol and/or menthol The weight ratio to the pharmaceutically acceptable carrier is from 1:1 to 20.

7. The pharmaceutical composition according to claim 5, wherein the solid dispersion of borneol and/or menthol is prepared as follows: a prescribed amount of borneol and/or menthol and a pharmaceutically acceptable carrier are weighed It is dissolved in an organic solvent and volatilized to remove the organic solvent.

The pharmaceutical composition according to claim 7, wherein the volatile organic solvent is removed at 20 to 80 °C.

The pharmaceutical composition according to any one of claims 6 to 8, wherein the pharmaceutically acceptable carrier is selected from the group consisting of polyethylene glycols having a molecular weight of more than 1000, polyvinylpyrrolidone, and poloxamer 188. , ethyl cellulose, used alone or in combination.

The pharmaceutical composition according to claim 7 or 8, wherein the organic solvent is selected from the group consisting of methanol, ethanol, acetone, isopropanol, n-butanol, dichloromethane, trichloromethane, n-hexane, and cyclohexane. Ethyl acetate, ethyl acetate, tetrahydrofuran, used alone or in combination.

The pharmaceutical composition according to claim 5, wherein the borneol and/or menthol cyclodextrin inclusion compound, borneol And/or the weight ratio of menthol to cyclodextrin is 1:1 to 10.

The pharmaceutical composition according to claim 5, wherein the borneol and/or menthol cyclodextrin inclusion compound is prepared according to the following method: Weigh a prescribed amount of borneol and/or menthol, dissolved in In an appropriate amount of aqueous organic solvent, a borneol and/or menthol solution is obtained, and a cyclodextrin is weighed to prepare a saturated aqueous solution of cyclodextrin; the mixture is mixed by agitation or grinding to make the cyclodextrin inclusion borneol And/or menthol, dried under vacuum at low temperature to a solid, ground, washed, and air-dried to obtain a clathrate powder.

The pharmaceutical composition according to claim 12, wherein the agitation mixing is carried out by slowly adding borneol and/or menthol solution to a saturated aqueous solution of cyclodextrin under stirring, and stirring is continued until A cyclodextrin inclusion complex of borneol and/or menthol.

The pharmaceutical composition according to claim 13, wherein the agitation is carried out at 20 to 80 ° C at a stirring speed of 100 to 2000 rpm.

15. The pharmaceutical composition according to claim 13, wherein the stirring is continued for 10 to 200 minutes.

16. The pharmaceutical composition according to claim 12, wherein the grinding and mixing is carried out by adding borneol and/or menthol solution and a saturated aqueous solution of cyclodextrin to a grinder, and thoroughly grinding and mixing to form a viscous paste. Things.

17. The pharmaceutical composition according to claim 16, wherein the grinding and mixing is carried out for 60 to 400 minutes.

The pharmaceutical composition according to any one of claims 11 to 17, wherein the cyclodextrin is selected from a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β- Cyclodextrin, 6-glucosyl-β-cyclodextrin, used alone or in combination.

The pharmaceutical composition according to any one of claims 12 to 17, wherein the aqueous organic solvent is selected from the group consisting of methanol, ethanol, acetone, isopropanol, n-butanol, ethyl acetate, tetrahydrofuran, used alone or in combination use.

The pharmaceutical composition according to claim 5, wherein the borneol and/or menthol microspheres (capsules) are composed of borneol and/or menthol, a capsule and an emulsifier, and the weight ratio thereof is 1. : 1~10 _: 0.01~5.

The pharmaceutical composition according to claim 20, wherein the capsule material is an acrylic resin, ethyl cellulose, used alone or in combination.

The pharmaceutical composition according to claim 20, wherein the emulsifier is a fatty acid sucrose ester, gelatin, gum arabic, used alone or in combination. ,

23. The pharmaceutical composition according to claim 5, wherein the borneol and/or menthol microspheres (capsules) are prepared as follows: Weigh a prescribed amount of borneol and/or menthol and capsule material, The two are co-dissolved in an aqueous organic solvent to obtain an aqueous organic solution; the emulsifier is weighed and formulated into an aqueous emulsifier; under stirring, the aqueous organic solution is quickly poured into an aqueous emulsifier solution, and fully stirred to form a microsphere. (sac), filtered, vacuum dried to a solid at low temperature, sieved, that is.

The pharmaceutical composition according to claim 23, wherein the aqueous emulsifier has a concentration of 0.1 to 0.5 g/L.

The pharmaceutical composition according to claim 23, wherein the stirring speed is 50 to 2000 rpm.

The pharmaceutical composition according to claim 23, wherein the aqueous organic solvent is ethanol, acetone, isopropanol, n-butanol, ethyl acetate, tetrahydrofuran, used alone or in combination.

27. A formulation for treating glioma, wherein the formulation comprises temozolomide, borneol and/or menthol cured and a pharmaceutically acceptable carrier.

28. The preparation according to claim 27, which is selected from the group consisting of pills, pills, capsules, granules, tablets, suspensions, injections, syrups, elixirs, powders, elixirs, topical medicinal preparations. Any one of a solution, a spray, and a suppository.

29. The formulation of claim 28, wherein the formulation is a tablet or capsule.

30. The formulation of claim 29, comprising a temozolomide, borneol and/or mentholic curative, a disintegrant, a diluent, a binder, and a lubricant.

31. The formulation of claim 30, wherein the diluent is selected from the group consisting of starch, sucrose, lactose, dextrin, microcrystalline cellulose, calcium sulfate, alone or in combination.

32. The formulation of claim 30, wherein the disintegrant is selected from the group consisting of sodium carboxymethyl starch, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, alone or Mixed use.

33. The formulation of claim 30, wherein the binder is a starch slurry having a concentration of from 2% to 10%.

34. The formulation of claim 30, wherein the lubricant is selected from the group consisting of magnesium stearate, micronized silica gel, talc, used alone or in combination.

35. The preparation according to claim 30, which has the composition as follows - temozolomide 0.5 to 25.0 parts by weight

Borneol and / or menthol cured product 1.0~50.0 parts by weight

Thinner 7.0~95.5 parts by weight

Disintegrant 0.5-8.0 parts by weight

Adhesive 1.0-5.0 parts by weight

Lubricant 0.5-5.0 parts by weight

36. The formulation of claim 31, which has the composition - temozolomide 5.0 to 10.0 parts by weight

Borneol and / or menthol cured product 8.0-25.0 parts by weight

Thinner 55.0~83.2 parts by weight

Disintegrator 1.0~3.0 parts by weight

Adhesive 2.0-4.0 parts by weight

Lubricant 0.8~3.0 parts by weight

37. A method of preparing a formulation according to any one of claims 30-36, comprising the steps of: weighing a prescribed amount of temozolomide, borneol and/or menthol cured, mixing, adding a diluent, a disintegrant, Mix well, add binder, granulate, add lubricant, mix, dry, whole, tablet or capsule.

38. A method of preparing a formulation according to any one of claims 30-36, comprising the steps of: weighing a prescribed amount of temozolomide, adding a diluent, a disintegrant, mixing well, adding a binder, granulating, Add lubricant, mix, dry, and granulate; weigh borneol and/or menthol solidified in organic solvent to make a solution, spray this solution evenly on the surface of the granules, dry naturally, compress or encapsulate.

The preparation method according to claim 38, wherein the organic solvent for dissolving the borneol and/or the menthol cured product is ethanol.