A novel formulation of temozolomide and uses thereof

Abstract

The application belongs to the field of pharmaceutical preparations and relates to a novel temozolomide preparation and use thereof, and the novel temozolomide preparation is a temozolomide sustained-release granule.The temozolomide sustained-release granule provided by the application contains the following components: 10-50 parts by weight of temozolomide, 5-20 parts by weight of sustained-release material I, 30-60 parts by weight of cyclodextrin, 20-50 parts by weight of sustained-release material II, 5-15 parts by weight of a pore-forming agent, 0.5-2 parts by weight of an anti-sticking agent, 80-150 parts by weight of a filler, 5-20 parts by weight of a disintegrant, 5-15 parts by weight of a binder, and 5-30 parts by weight of a flavoring agent.The temozolomide sustained-release granule prepared by the application has obvious sustained-release effect, can effectively maintain stable blood drug concentration, reduces the frequency of use and the amount of medication, and improves the compliance of patients.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and relates to a novel temozolomide preparation and use thereof. BACKGROUND

[0002] Glioblastoma is the most common primary malignant brain tumor, accounting for about 12-15%. Glioblastoma can occur at any age, but is mainly seen in adults, with the peak age of onset being 45-70 years old. It is more common in men than in women, with a ratio of 3:2.

[0003] Temozolomide is used for the treatment of adult intractable glioblastoma multiforme, and was approved by FDA on August 11, 1999 and marketed in the United States. Temozolomide (TMZ) is a new type of oral broad-spectrum antitumor drug with low toxicity, high activity and good oral absorption. As a first-line drug for glioma chemotherapy, it has benefited millions of patients with malignant glioma. Oral administration of temozolomide rapidly decomposes into active substance MTIC under neutral or alkaline conditions, and decomposes faster under alkaline conditions. TMZ has no direct antitumor activity, rapidly non-enzymatically converts to active compound MTIC under physiological PH conditions, exerts a role on DNA methylation, causes single or double strand breakage, blocks DNA replication, and causes tumor cell death.

[0004] Temozolomide can rapidly penetrate the blood-brain barrier, and the drug concentration in the cerebrospinal fluid is 30% of the plasma concentration, and the concentration in tumor cells is much higher than that in normal cells, so it can kill tumor cells while protecting normal tissues to the maximum extent.

[0005] The currently marketed oral temozolomide preparation is only temozolomide capsules. For patients with difficulty swallowing, the capsules are generally opened, and the powder in the capsules is dissolved in an acidic solution for the patient to take. However, when preparing the drug solution, protective measures must be taken: wear a mask when preparing the drug to prevent the flying and inhalation of drug powder; wear disposable gloves to avoid direct contact with the drug powder; the cup and spoon used for preparation are recommended to be cleaned and disinfected before use; and the empty capsules and gloves after preparation should not be placed randomly, and the drug use is more complicated.

[0006] Chinese patent CN201711380247.0 discloses a temozolomide sustained-release capsule and a preparation method thereof. The prepared temozolomide sustained-release capsule can release the drug continuously within 12 hours, which can reduce the frequency of drug use by patients. However, the preparation is still a capsule, and for patients with difficulty swallowing, the drug use is still complicated. SUMMARY

[0007] To overcome the defects of the prior art, the main purpose of the present application is to provide a temozolomide sustained-release granules, which can release the drug smoothly within 12 hours, solve the problem of short half-life of temozolomide and unstable blood drug concentration when taking medicine, and the dosage form of granules is convenient for patients with difficulty in swallowing.

[0008] The present application adopts the following technical solutions to achieve the above-mentioned purposes:

[0009] A temozolomide sustained-release granules is prepared by the following steps:

[0010] Step A, take temozolomide and add it to the molten state of sustained-release material I, cool and grind, add cyclodextrin to prepare inclusion compound, and reserve;

[0011] Step B, take sustained-release material II, pore-forming agent and anti-adhesion agent to prepare a sustained-release coating liquid, spray it on the surface of the inclusion compound obtained in step A, dry, and then add filler, disintegrant, binder and flavoring agent to wet granulation, and the temozolomide sustained-release granules is obtained.

[0012] Specifically, the above-mentioned temozolomide sustained-release granules contains the following components:

[0013] Temozolomide 10-50 parts by weight

[0014] Sustained-release material I 5-20 parts by weight

[0015] Cyclodextrin 30-60 parts by weight

[0016] Sustained-release material II 20-50 parts by weight

[0017] Pore-forming agent 5-15 parts by weight

[0018] Anti-adhesion agent 0.5-2 parts by weight

[0019] Filler 80-150 parts by weight

[0020] Disintegrant 5-20 parts by weight

[0021] Binder 5-15 parts by weight

[0022] Flavoring agent 5-30 parts by weight

[0023] Further, the above-mentioned temozolomide granules contains the following components:

[0024] Temozolomide 10-50 parts by weight

[0025] Sustained-release material I 8-15 parts by weight

[0026] Cyclodextrin 35-45 parts by weight

[0027] Sustained release material II 30-40 parts by weight

[0028] Pore forming agent 10-12 parts by weight

[0029] Anti-sticking agent 1-1.8 parts by weight

[0030] Filling agent 100-120 parts by weight

[0031] Disintegrant 10-15 parts by weight

[0032] Binder 8-12 parts by weight

[0033] Flavoring agent 10-18 parts by weight

[0034] The sustained release material I is a combination of one or more of Carnauba wax, glyceryl monostearate, hydrogenated vegetable oil, beeswax, sodium alginate, acrylic resin, etc.; preferably acrylic resin.

[0035] The cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0036] The sustained release material II is a combination of one or more of hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polymethacrylate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate acetate, etc.; preferably a mixture of polymethacrylate and hydroxypropyl methyl cellulose phthalate; further preferably, the use ratio of the polymethacrylate and hydroxypropyl methyl cellulose phthalate is 1:3-:10; more preferably, the use ratio is 1:4-8.

[0037] The pore forming agent is a combination of one or more of polyethylene glycol, hydroxypropyl methyl cellulose, lactose, talc, sucrose, etc.

[0038] The anti-sticking agent is a combination of one or more of talc, corn starch, silicon dioxide, magnesium stearate, etc.

[0039] The filling agent is a combination of one or more of starch, pregelatinized starch, microcrystalline cellulose, lactose, calcium carbonate, sorbitol, mannitol, etc.; preferably a mixture of microcrystalline cellulose and mannitol; further preferably, the use ratio of the microcrystalline cellulose and mannitol is 1:6-15; more preferably, the use ratio is 1:8-12.

[0040] The disintegrant is a combination of one or more of sodium carboxymethyl starch, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, povidone, cross-linked povidone, etc.; preferably a mixture of carboxymethyl cellulose and cross-linked sodium carboxymethyl cellulose; further preferably, the use ratio of the carboxymethyl cellulose and cross-linked sodium carboxymethyl cellulose is 1:1-10; more preferably, the use ratio is 1:5-8.

[0041] The binder is a combination of one or more of pregelatinized starch, lactose, starch slurry, sucrose, povidone, etc.

[0042] The flavoring agent is a combination of one or more of aspartame, cyclamate, vanillin, edible flavoring, sucrose, etc.

[0043] The present invention has the following beneficial effects:

[0044] The temozolomide sustained-release granules prepared by the present invention are prepared by using a technology of encapsulating temozolomide and part of the sustained-release material with cyclodextrin, and then coating the sustained-release material. The components act synergistically to achieve sustained, long-lasting and stable release of temozolomide. Compared with ordinary granules or other types of sustained-release granules, the temozolomide sustained-release granules have a longer action time and a more obvious sustained-release effect, can effectively maintain a stable blood drug concentration, reduce the number of times and dosage of the drug, and are granules, so they are easy for patients with dysphagia to take, improve patient compliance, and have a simple process and are convenient for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Attachment Figure 1 Comparison of the dissolution rates of temozolomide granules in various examples DETAILED DESCRIPTION

[0046] The present invention is further illustrated below with reference to specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. After reading the present invention, modifications of various equivalent forms of the present invention made by those skilled in the art all fall within the scope of protection of the claims of this application.

[0047] Example 1 Preparation of Temozolomide Sustained-Release Granules

[0048] 12g of acrylic resin is heated to a molten state, 20g of temozolomide is added, the mixture is mixed, cooled, and ground to prepare a drug-containing packaging material; 40g of hydroxypropyl-β-cyclodextrin is added with an appropriate amount of water and ground evenly, the drug-containing packaging material is added and mixed evenly, ground into a paste, dried at low temperature, washed with ethanol, and dried again to prepare an inclusion compound; 6g of polymethacrylate, 30g of hydroxypropyl methylcellulose phthalate, 12g of polyethylene glycol, and 1.5g of talc are prepared to prepare a sustained-release coating solution, which is sprayed on the surface of the inclusion compound. After drying, 11g of microcrystalline cellulose, 99g of mannitol, 2g of carboxymethyl cellulose, 12g of cross-linked sodium carboxymethyl cellulose, 10g of povidone, 5g of aspartame, and 10g of vanillin are added and mixed evenly, and granulated by a wet method to obtain temozolomide sustained-release granules.

[0049] Example 2 Preparation of Temozolomide Sustained-Release Granules

[0050] Take 15 g acrylic resin heated to a molten state, add 20 g of temozolomide, mix, cool, fine, made of drug-containing package material; 35 g of hydroxypropyl-β-cyclodextrin plus water, add the drug-containing package material, mix, grind to paste, low temperature drying, ethanol washing, drying, preparation of inclusion compound; take 4 g of polymethyl methacrylate, 32 g of hydroxypropyl methyl cellulose phthalate, 10 g of polyethylene glycol, 1.8 g of talc, made of sustained-release coating liquid, sprayed on the surface of the inclusion compound, dried, add 10 g of microcrystalline cellulose, 90 g of mannitol, 1 g of carboxymethyl cellulose, 10 g of cross-linked sodium carboxymethyl cellulose, 8 g of povidone, 5 g of aspartame, 5 g of vanillin, mix, wet granulation, temozolomide sustained-release granules.

[0051] Example 3 Temozolomide sustained-release granules preparation

[0052] Take 15 g acrylic resin heated to a molten state, add 20 g of temozolomide, mix, cool, fine, made of drug-containing package material; 35 g of hydroxypropyl-β-cyclodextrin plus water, add the drug-containing package material, mix, grind to paste, low temperature drying, ethanol washing, drying, preparation of inclusion compound; take 4 g of polymethyl methacrylate, 32 g of hydroxypropyl methyl cellulose phthalate, 10 g of polyethylene glycol, 1.8 g of talc, made of sustained-release coating liquid, sprayed on the surface of the inclusion compound, dried, add 10 g of microcrystalline cellulose, 90 g of mannitol, 1 g of carboxymethyl cellulose, 10 g of cross-linked sodium carboxymethyl cellulose, 8 g of povidone, 5 g of aspartame, 5 g of vanillin, mix, wet granulation, temozolomide sustained-release granules.

[0053] Example 4 Temozolomide sustained-release granules preparation

[0054] Take 15 g acrylic resin heated to a molten state, add 20 g of temozolomide, mix, cool, fine, made of drug-containing package material; 35 g of hydroxypropyl-β-cyclodextrin plus water, add the drug-containing package material, mix, grind to paste, low temperature drying, ethanol washing, drying, preparation of inclusion compound; take 4 g of polymethyl methacrylate, 32 g of hydroxypropyl methyl cellulose phthalate, 10 g of polyethylene glycol, 1.8 g of talc, made of sustained-release coating liquid, sprayed on the surface of the inclusion compound, dried, add 10 g of microcrystalline cellulose, 90 g of mannitol, 1 g of carboxymethyl cellulose, 10 g of cross-linked sodium carboxymethyl cellulose, 8 g of povidone, 5 g of aspartame, 5 g of vanillin, mix, wet granulation, temozolomide sustained-release granules.

[0055] Example 5 Temozolomide sustained-release granules preparation

[0056] Take 5g acrylic resin heated to a molten state, add 20g temozolomide, mix, cool, grind, made of drug-containing package material; 45g hydroxypropyl-β-cyclodextrin plus water, add the drug-containing package material, mix, grind to paste, low temperature drying, ethanol washing, drying, preparation of inclusion compound; take 10g polymethyl methacrylate, 30g hydroxypropyl methyl cellulose phthalate, 5g polyethylene glycol, 1g talc, made of sustained-release coating liquid, sprayed on the surface of the inclusion compound, dried, add 8g microcrystalline cellulose, 120g mannitol, 2g carboxymethyl cellulose, 16g cross-linked sodium carboxymethyl cellulose, 5g povidone, 10g aspartame, 20g vanillin mix, wet granulation, temozolomide sustained-release granules.

[0057] Example 6 Temozolomide sustained-release granules preparation

[0058] Take 20g acrylic resin heated to a molten state, add 20g temozolomide, mix, cool, grind, made of drug-containing package material; 60g hydroxypropyl-β-cyclodextrin plus water, add the drug-containing package material, mix, grind to paste, low temperature drying, ethanol washing, drying, preparation of inclusion compound; take 10g polymethyl methacrylate, 40g hydroxypropyl methyl cellulose phthalate, 15g polyethylene glycol, 0.5g talc, made of sustained-release coating liquid, sprayed on the surface of the inclusion compound, dried, add 10g microcrystalline cellulose, 80g mannitol, 7.5g carboxymethyl cellulose, 7.5g cross-linked sodium carboxymethyl cellulose, 15g povidone, 2.5g aspartame, 2.5g vanillin mix, wet granulation, temozolomide sustained-release granules.

[0059] Example 7 Temozolomide sustained-release granules preparation

[0060] Take 12g Brazil palm wax heated to a molten state, add 20g temozolomide, mix, cool, grind, made of drug-containing package material; 30g hydroxypropyl-β-cyclodextrin plus water, add the drug-containing package material, mix, grind to paste, low temperature drying, ethanol washing, drying, preparation of inclusion compound; take 3g polymethyl methacrylate, 30g hydroxypropyl methyl cellulose phthalate, 12g polyethylene glycol, 1.5g talc, made of sustained-release coating liquid, sprayed on the surface of the inclusion compound, dried, add 10g microcrystalline cellulose, 120g mannitol, 20g carboxymethyl starch sodium, 10g sucrose, 15g sweetener mix, wet granulation, temozolomide sustained-release granules.

[0061] Example 8 Temozolomide sustained-release granules preparation

[0062] Take 12 g acrylic resin heated to a molten state, add 10 g temozolomide, mix, cool, fine, made of drug-containing package material; 40 g hydroxypropyl-β-cyclodextrin plus appropriate amount of water, add the drug-containing package material mix, grinding to paste, low temperature drying, ethanol washing, drying again, preparation of inclusion compound; take 36 g carboxymethylcellulose sodium, 12 g polyethylene glycol, 1.5 g talc, made of sustained-release coating liquid, sprayed on the surface of the inclusion compound, dried, add 12 g pregelatinized starch, 108 g lactose, 5 g crosslinked povidone, 10 g starch paste, 15 g sucrose mix, wet granulation, temozolomide sustained-release granules.

[0063] Example 9 Temozolomide sustained-release granules preparation

[0064] Take 12 g acrylic resin heated to a molten state, add 50 g temozolomide, mix, cool, fine, made of drug-containing package material; 40 g hydroxypropyl-β-cyclodextrin plus appropriate amount of water, add the drug-containing package material mix, grinding to paste, low temperature drying, ethanol washing, drying again, preparation of inclusion compound; take 36 g carboxymethylcellulose sodium, 12 g polyethylene glycol, 1.5 g talc, made of sustained-release coating liquid, sprayed on the surface of the inclusion compound, dried, add 15 g calcium carbonate, 135 g sorbitol, 2 g carboxymethylcellulose, 12 g crosslinked carboxymethylcellulose sodium, 10 g lactose, 5 g sucrose, 10 g lemon flavor mix, wet granulation, temozolomide sustained-release granules.

[0065] Comparative Example 1 Temozolomide sustained-release granules preparation

[0066] Take 12 g acrylic resin, 20 g temozolomide, 11 g microcrystalline cellulose, 99 g mannitol, 2 g carboxymethylcellulose, 12 g crosslinked carboxymethylcellulose sodium, 10 g povidone, 5 g aspartame, 10 g vanillin mix, wet granulation, made of drug-containing granules; take 6 g polymethyl acrylate, 30 g hydroxypropyl methyl cellulose phthalate, 12 g polyethylene glycol, 1.5 g talc, made of sustained-release coating liquid, sprayed on the surface of the inclusion compound, dried, temozolomide sustained-release granules.

[0067] Comparative Example 2 Temozolomide sustained-release granules preparation

[0068] Take 40 g of hydroxypropyl-β-cyclodextrin and add appropriate amount of water to make a paste, add 20 g of temozolomide and mix well, grind to a paste, dry at low temperature, wash with ethanol, and dry again to prepare the inclusion complex; take 6 g of polymethacrylate, 30 g of hydroxypropyl methylcellulose phthalate, 12 g of polyethylene glycol, 1.5 g of talc, and prepare a sustained-release coating liquid, spray it on the surface of the inclusion complex, dry it, and then add 11 g of microcrystalline cellulose, 99 g of mannitol, 2 g of carboxymethyl cellulose, 12 g of cross-linked sodium carboxymethyl cellulose, 10 g of povidone, 5 g of aspartame, and 10 g of vanillin to mix well, and then wet granulation is performed to obtain the temozolomide sustained-release granules.

[0069] Preparation of temozolomide granules in comparative example 3

[0070] Take 20 g of temozolomide, 11 g of microcrystalline cellulose, 99 g of mannitol, 2 g of carboxymethyl cellulose, 12 g of cross-linked sodium carboxymethyl cellulose, 10 g of povidone, 5 g of aspartame, and 10 g of vanillin to mix well, and then wet granulation is performed to prepare temozolomide granules.

[0071] Effect verification

[0072] According to the dissolution and release determination method in the fourth part of the Chinese Pharmacopoeia (2020 edition), the temozolomide granules obtained in examples 1-4 and comparative examples 1-3 are taken as the dissolution medium, the rotation speed is 50 revolutions / min, the temperature is 37±1℃, and the samples are taken at 0.5h, 1h, 2h, 4h, 6h, 10h, and 12h, respectively, to determine the dissolution rate, and the results are shown in the following table. Figure 1 .

[0073] Result analysis: the temozolomide granules prepared in comparative example 3 are ordinary granules, which are all dissolved within 1 hour; the temozolomide sustained-release granules prepared in examples 1-4 can be continuously and stably released within 12 hours; the temozolomide sustained-release granules prepared in comparative examples 1 and 2 also have a sustained-release effect, but they can only be continuously released within 6-8 hours and have a burst release phenomenon.

[0074] It can be seen that the temozolomide sustained-release granules prepared in the present application have a longer action time, a more obvious sustained-release effect, can effectively maintain a stable blood drug concentration, reduce the frequency and amount of use, are granules, are convenient for patients with difficulty in swallowing to take, improve the compliance of patients, and have a simple process and are convenient for industrialized production.

Claims

1. A novel formulation of temozolomide characterized in that, The preparation is sustained-release granules, which is prepared by the following steps: Step A, take temozolomide into the melting state of sustained-release material I, cool and grind, add cyclodextrin to prepare inclusion compound, ready for use; Step B, take sustained-release material II, pore-forming agent, anti-adhesion agent to prepare sustained-release coating liquid, spray on the surface of the inclusion compound obtained in step A, dry, then add filler, disintegrant, binder, flavoring agent, wet granulation, temozolomide sustained-release granules are obtained; wherein the sustained-release granules contain the following components: Temozolomide 10-50 parts by weight Sustained-release material I 5-20 parts by weight Cyclodextrin 30-60 parts by weight Sustained-release material II 20-50 parts by weight Pore-forming agent 5-15 parts by weight Anti-adhesion agent 0.5-2 parts by weight Filler 80-150 parts by weight Disintegrant 5-20 parts by weight Binder 5-15 parts by weight Flavoring agent 5-30 parts by weight The sustained-release material I is acrylic resin, the cyclodextrin is hydroxypropyl-β-cyclodextrin; the sustained-release material II is a mixture of polymethyl methacrylate and hydroxypropyl methyl cellulose phthalate, the use ratio of the polymethyl methacrylate and hydroxypropyl methyl cellulose phthalate is 1:3-10; the filler is a mixture of microcrystalline cellulose and mannitol, the use ratio of the microcrystalline cellulose and mannitol is 1:6-15; the disintegrant is a mixture of carboxymethyl cellulose and cross-linked sodium carboxymethyl cellulose, the use ratio of the carboxymethyl cellulose and cross-linked sodium carboxymethyl cellulose is 1:1-10.

2. A novel formulation of temozolomide as claimed in claim 1, wherein, contains the following components: Temozolomide 10-50 parts by weight Sustained-release material I 8-15 parts by weight Cyclodextrin 35-45 parts by weight Sustained-release material II 30-40 parts by weight Pore-forming agent 10-12 parts by weight Anti-adhesion agent 1-1.8 parts by weight Filler 100-120 parts by weight Disintegrant 10-15 parts by weight Binder 8-12 parts by weight Flavoring agent 10-18 parts by weight.

3. A novel formulation of temozolomide as claimed in claim 1, wherein, The use ratio of the polymethyl methacrylate and hydroxypropyl methyl cellulose phthalate is 1:4-8.

4. A novel formulation of temozolomide as claimed in claim 1, wherein, The use ratio of the microcrystalline cellulose and mannitol is 1:8-12; the use ratio of the carboxymethyl cellulose and cross-linked sodium carboxymethyl cellulose is 1:5-8.

5. A novel formulation of temozolomide as claimed in any one of claims 1 to 3, wherein, The pore-forming agent is a combination of one or more of polyethylene glycol, hydroxypropyl methyl cellulose, lactose, talc and sucrose; the anti-adhesion agent is a combination of one or more of talc, corn starch, silicon dioxide and magnesium stearate; the binder is a combination of one or more of pregelatinized starch, lactose, starch paste, sucrose and povidone; the flavoring agent is a combination of one or more of aspartame, cyclamate, vanillin, food flavor and sucrose.

6. The use of the preparation of any one of claims 1-3 in the preparation of a medicament for treating primary malignant brain tumors.

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