MXPA00012079A

MXPA00012079A - Cyclophosphamide coated tablets

Info

Publication number: MXPA00012079A
Application number: MXPA/A/2000/012079A
Authority: MX
Inventors: Jurgen Engel; Dieter Sauerbier; Jurgen Rawert; Burkhard Wichert
Original assignee: Asta Medica Aktiengesellschaft
Priority date: 1998-06-15
Filing date: 2000-12-06
Publication date: 2002-03-05

Abstract

The invention relates to coated tablets having cyclophosphamide as active substance, containing in the core cyclophosphamide, one or more fillers, one or several dry binding agents but no pre-swollen starches, flow regulation agents and lubricants. In a preferred embodiment of the invention, the core of the film tablet contains lactose monohydrate, D-mannite or CaHPO4 as fillers, non-pre-swollen corn starch or micro fine cellulose as dry binding agents, highly dispersed silicon oxide as flow regulation agents and magnesium stearate, stearic acid, glycerin palmitostearate, polyethylene glycol, talc or glycerin monobehenate as lubricants.

Description

COATED CYCLOPHOSPHAMIDE TABLETS Description of the invention The invention relates to coated cyclophosphamide tablets, as well as to a method for their preparation. The invention has application in the pharmaceutical industry. Cyclophosphamide is a remedy with broad antitumor spectrum, introduced for decades in chemotherapy for the treatment of solid tumors such as breast cancer, bronchial cancer as well as haemoblasts. The medicinal preparations are so far tablets, dragees, as well as mainly lyophilized with various auxiliary substances, such as mannitol or urea. EP 0519099 discloses tablets containing cyclophosphamide and pre-foamed starch, manufactured by a direct tableting process. Because the cyclophosphamide is harmful to health and therefore a direct contact with this substance represents a potential risk, the tablets prepared according to EP 0519099 are used as cores for wrapping tablets, and thus are wrapped by a second tableted. This process is technically complex. In addition, special tableting machines are required for the manufacture of wrapping tablets. Accordingly, there is a need for a simple and inexpensive preparation of a solid oral drug preparation containing cyclophosphamide. In this it is important to consider that medicinal preparations must be wrapped to avoid direct contact with the cytotoxic active ingredient. Surprisingly, it was possible to prepare coated tablets containing cyclophosphamide, without using pre-foamed starch. Suitable auxiliaries were selected based on the compatibility investigations listed in Example I. Surprisingly it was found that the stability of cyclophosphamide is rather regular in the presence of pre-foamed starch. It was also surprising that the coated tablets show sufficient stability despite the fact that, due to the process, the active principle is subjected to humidity and heat during the coating process. Example 1 Investigation of the compatibility of cyclophosphamide with various tableting substances. 53.5 mg of cyclophosphamide and 86.5 mg (of auxiliary substance 1-10) and 3.0 mg (of auxiliary substance 11-18) were mixed and b in each case. The storage of the tablets was carried out at 31 ° C for 6 months. The decomposition of the active substance was carried out by determination of the chloride. The results are summarized in the following table. continuation of the table depending on the type Example 2 Preparation of tablet cores (50 mg of cyclophosphamide) Direct tabletting 0.535 mg of the osfamide cycle, 0.390 mg of lactose monohydrate, 0.400 mg of microcrystalline cellulose, 0.200 mg of corn starch, 0.040 mg of talc and 0.5 mg are sieved and homogenized. 0.020 mg of highly dispersed silicon dioxide. Next, 0.015 mg of magnesium stearate is added and mixed. The dough prepared in this way is made into tablets: Weight: 160 mg Hardness: > 30 N Decomposition: < 10 minutes.

Example 3 Preparation of coated tablets (50 mg of cyclophosphamide) 11.83 g of polyethylene glycol and 2.37 g of polysorbitol 80 are dissolved in 75.21 g of water. 1.9 g of sodium carboxymethylcellulose are dissolved in 80.0 g of water. The solutions come together. Then 23.67 g of talc, 23.67 g of titanium dioxide and 0.24 g of simeticone are added and homogenized. Subsequently, 17.73 g of a water dispersion of copolymerized acrylic acid ethyl ester / methacrylic acid methyl ester are added. Next, the cores of the tablets are sprayed with the prepared suspension, with a suitable device. Theoretical weight of a coated tablet 166 mg Example 4 Investigation of the stability of coated cyclophosphamide tablets.

With a storage to < 25 ° C a stability of the coated tablets of up to 3 years is expected.

Claims

CLAIMS 1. Coated tablet comprising a core of the tablet containing cyclophosphamide as an active ingredient, as well as one or more fillers, one or more dry binders, one or more flow regulators, one or more lubricants and one suitable coating film, characterized in that in the core of the tablet at least one of the fillers is lactose monohydrate and as a dry binder it does not contain pre-foamed starch.
2. A coated tablet according to claim 1, characterized in that for the core of the tablet the filler substance (s) is selected from the group comprising lactose monohydrate, mannitol D and potassium phosphate, the binder (s) (s) dry are selected from the group comprising non-pre-fluffed corn starch and microcrystalline cellulose, the flux regulating agent (s) is (are) selected from the group comprising dioxides of highly dispersed silicon, and the lubricant (s) is (are) selected from the group consisting of magnesium stearate, stearic acid, palmito-glycerin stearate, polyethylene glycol, talc and glycerin monobehenate.
3. Coated tablets comprising a core of the tablet and a suitable coating film, characterized in that the core contains as an active principle cyclophosphamide and as auxiliary substances lactose monohydrate, non-pre-foamed corn starch, microcrystalline cellulose, high silicon dioxide dispersed, magnesium stearate and talc. Coated tablet according to one of claims 1 to 3, characterized in that 1 part of cyclophosphamide in the core of the tablet comprises, in each case, the weight: 0.2-1.5 parts of lactose monohydrate 0.2-1.5 parts of microcrystalline cellulose 0.1-1.5 parts of corn starch not pre-foamed 0.01-1.5 parts of talc 0.01-0.1 parts of highly dispersed silicon dioxide, and 0.01-0.1 parts of magnesium stearate. Coated tablet according to one of claims 1 to 4, characterized in that 1 part of cyclophosphamide in the core of the tablet comprises, in each case referred to weight: 0.5-1 parts of lactose monohydrate 0.5-1 parts of microcrystalline cellulose 0.2-0.7 parts of corn starch not pre-foamed 0.05-0.08 parts of talc 0.01-0.05 parts of highly dispersed silicon dioxide, and

0. 01-0.05 parts of magnesium stearate. Coated tablet according to one of claims 1 to 5, characterized in that 1 part of cyclophosphamide in the core of the tablet comprises, in each case referred to weight: 0.73 parts of lactose monohydrate 0.74-0.75 parts of microcrystalline cellulose 0.37 parts of non-pre-foamed corn starch 0.07-0.075 parts of talc 0.037-0.04 parts of highly dispersed silicon dioxide, and 0.028-0.03 parts of magnesium stearate. Coated tablet according to one of claims 1 to 6, characterized in that the coating film comprises substances that are selected from the group comprising polyethylene glycol, polysorbitol 80, sodium carboxymethylcellulose, talc, titanium dioxide, simethicone, copolymerized ethyl ester of the acrylic acid-methacrylic acid methyl ester. 8. Tablet core containing cyclophosphamide as an active substance, as well as one or more fillers, one or more dry binders, one or more flow regulating agents and one or more lubricants, characterized in that at least one of the substances of filler is lactose monohydrate and as a dry binder it does not contain pre-foamed starch. Tablet core according to claim 8, characterized in that the filler substance (s) is (are) selected from the group comprising lactose monohydrate, mannitol D and potassium phosphate, the dry binder (s) selected from the group comprising non-pre-foamed corn starch and microcrystalline cellulose, the creep regulatory agent (s) is (are) selected from the group comprising highly dispersed silicon dioxides, and the lubricant (s) is selected from the group comprising magnesium stearate , stearic acid, palmito-glycerin stearate, polyethylene glycol, talc and glycerin monobehenate. 10. A tablet nucleus characterized in that it comprises, as an active principle, cyclophosphamide and, as auxiliary substances, lactose monohydrate, non-pre-foamed corn starch, microcrystalline cellulose, highly dispersed silicon dioxide, magnesium stearate and talc. Tablet core according to one of claims 8 to 10, characterized in that 1 part of cyclophosphamide comprises, in each case referred to weight: 0.2-1.5 parts of lactose monohydrate 0.2-1.5 parts of microcrystalline cellulose

0. 1-1.5 parts of corn starch not pre-foamed 0.01-1.5 parts of talc 0.01-0.1 parts of highly dispersed silicon dioxide, and 0.01-0.1 parts of magnesium stearate. Tablet core according to one of claims 8 to 11, characterized in that 1 part of cyclophosphamide comprises, in each case referred to weight: 0.5-1 parts of lactose monohydrate 0.5-1 parts of microcrystalline cellulose 0.2-0.7 parts of corn starch not pre-foamed 0.05-0.08 parts of talc 0.01-0.05 parts of highly dispersed silicon dioxide, and 0.01-0.05 parts of magnesium stearate. 13. Tablet core according to one of claims 8 to 12, characterized in that 1 part of cyclophosphamide comprises, in each case referred to weight: 0.73 parts of lactose monohydrate 0.74-0.75 parts of microcrystalline cellulose 0.37 parts of corn starch not pre-foamed 0.07-0.075 parts of talc 0.037-0.04 parts of highly dispersed silicon dioxide, and

0. 028-0.03 parts magnesium stearate. 14. Coated tablet, characterized in that it is obtained by providing a suitable coating film in a tablet core according to claims 8 to 13. 15. Coated tablet according to claim 14, characterized in that the coating film comprises substances that are selected from the group that it comprises polyethylene glycol, polysorbitol 80, sodium carboxymethylcellulose, talc, titanium dioxide, simethicone, copolymerized acrylic acid ethyl ester methacrylic acid methyl ester and water. 16. Method for manufacturing tablet cores according to claims 8 to 13, characterized in that it comprises respectively the steps of screening and collecting cyclophosphamide, the filler substance (s), the dry binder (s), the or the regulating agent (s) of the fluence and a part of the lubricant (s), homogenizing the mixture thus obtained, sifting and adding the remaining lubricant (s), mixing the mixture obtained in this way and compressing the mass obtained in this way to tablet cores. 17. Method according to claim 16, characterized in that in the step of sifting and gathering, talc is added as a lubricant and in the step of sifting and adding the remaining lubricants, magnesium stearate is added as a lubricant. 18. Method for the production of coated tablets, characterized in that the tablet cores obtained according to claims 16 or 17 are sprayed with a suitable coating suspension. The method according to claim 18, characterized in that the coating substance comprises substances that are selected from the group comprising polyethylene glycol, polysorbitol 80, sodium-carboxymethylcellulose, talc, titanium dioxide, simethicone, copolymerization of ethyl ester of acrylic acid-methyl ester of methacrylic acid and water.