Title of Invention	"AN ESSENTIALLY LACTOSE-FREE STABLE ORAL PHARMACEUTICAL COMPOSITION OF PHOSPHOLIPID DERIVATIVES"
Abstract	The present invention relates to stable pharmaceutical formulations of phospholipid derivatives. The compositions are non-hydroscopic, stable and easily manufactured, because they are lactose-free or at least not containing more lactose than 1 % per weight.

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The invention relates to oral dosage forms containing phospholipid derivatives. Background of the Invention: US Patent 4,837,023 discloses preparation of hard capsule form through suspending of Aerosil in solution of miltefosine in chloroform (1:1), evaporating of the solvent under vacuum, passing of dry mass through a 1 mm sieve and again drying in vacuum at 30°C for eliminating solvents residues. But Chloroform is classified as toxic and carcinogenic compound and thats why it is not approved by the regulatory agencies, for example the FDA in the USA. Hard dosage forms are known, containing miltefosine and excipients: diluting substances (fillers) - lactose, mannitol, calcium phosphates, microcrystalline cellulose and their mixtures; glidants - silicon dioxide, talc; lubricants - magnesium stearate and their mixtures in stated relations, as disclosed in the WO 99/37289. It is known that miltefosine is a highly hygroscopic phosphocholine substance, with a structure of zwitterion. That is why the excipients or the impurities contained in them could interfere with the active substance and do influence the analysis or stability of the medicinal form. A similar structure and similar properties possess phospholipid derivatives, which are described in EP 0 108 565 A, glycerol-phosphoryl choline derivatives (US Patent 4,493,832), phospholipid derivatives from US Patent 5,158,942, soybean phospholipids, Lecithin (the United States Pharmacopoeia), a-phosphatidyl choline, a-phosphatidyl-ethanolamine and alkyl phosphocholine. Summary of the Invention: The stability of a certain pharmaceutical product depends on various factors: compatibility of the active substance with the excipients, sensitivity to humidity and others. With the help of differential scanning calorimetry (DSC) are examined the possible interactions between the active ingredient and the excipients. An additional examination is earned out of the interaction by the method of thin-layer chromatography (TLC). Lactose exhibits some kind of reaction with miltefosine in the conditions of the DSC-test. In addition, Lactose exercises obstructive influence during the analysis of "related substances" by the method of thin-layer chromatography (TLC). On the basis of those data pharmaceutical compositious without!lactose are developed. There are included excipients with low content of moisture content, in correspondence with the hygroscopic properties of miltefosine. Detailed Description of the Invention: The scope of the invention is development of compositions for capsule forms, where the interaction between phospholipid and the excipients is avoided. Differential Scanning Calorimetry (DSC) is used for screening of excipients in drug-excipient compatibility studies. It is assumed that the thermal characteristics of mixtures are a sum of the individual components, if there is no interaction between the components. The studies were conducted on apparatus Mettler DSC 821e Module 1, software Star® system, in temperature interval from 80 to 280°C, heating speed. 10°C/min in air medium. At first the thermal characteristics of the pure substances were observed: miltefosine, microcrystalline cellulose PHI 12, lactose (spray dried), starch 1500 LM, sodium starch glycollate, corn starch Aerosil 200, talc. The results are shown in Table 1 and Fig.l: (Table Removed) The possible interactions are studied between the active ingredient and the excipients by DSC-thermograms of samples - physical mixtures in relation (3:1), also in relation in which they are in the capsule mixture. The measured thermal effects are shown in Table 2 and Fig. 2 to Fig. 4. (Table Removed) The thermogram of miltefosine shows two endotherms: endotherm of elimination of water at 95.42°C, corresponding to 1 mol hydrated water and endotherm, corresponding to melting at 251.57°C, followed by decomposition of the substance. With the mixture miltefosine/lactose the higher endotherm of melting of lactose and endotherm of melting of miltefosine merge in one endotherm of melting, which is indicative of interaction between the active and the excipients, probably formation of solid dispersion. It is also possible electrostatic interaction between the reactive OH-groups of lactose and zwitterion of miltefosine. An additional study has been carried out on the interaction of miltefosine with the excipients by the method of Thin-layer Chromatography (TLC). Mixtures of miltefosine are prepaied with each separate of the studied excipients, and also a reference standard of miltefosine. The same condition as the one stated in the study for "related substances" in medicinal form according to Ph.Eur. 2.2.27 "Thin-layer chromatography". Sorbent - Silicagel 60 F254 plate (Merck), with layertickness 0.25 mm. Test solution - 100 mg are dissolved in 4 ml of Chloroform. 20 µ1 are applied at the starting point. Mobile phase - Chloroform : methanol : sodium acetate solution (1 mol/1) in concentrated ammonium hydroxide = 70:40:10. Development - sprayed with cerium reactive. Evaluation - the plates are densitometerd at wavelength 530 nm (Densitometer Camag). The main spot in the chromatograms obtained at Rf ~ 0.38 corresponds to miltefosine. The specified impurities in the active substance (total 1.0%) are with Rf values higher than 0.38. All of the excipients with the exception of lactose exhibit properties of placebo, i.e. they do not show obstructive influence in the evaluation of miltefosine and do not show additional spots out of those specified for miltefosine. Just with the sample with lactose is observed one additional spot at the start (Rf ~ 0.0) and content ~ 0.5%. That fact confirms also the supposition for existence of interaction between miltefosine and lactose. The present invention ensures stable pharmaceutical compositions which do not contain lactose and which as a whole are non-hygroscopic and are with low content of humidity. The suitable excepients for such compositions is micricrystalline cellulose (Vivapur type 112) with low content of moisture ( Microcrystalline cellulose can be used in quantity from 20% to about 90% of the mass of the composition, it is preferable 60% to 85%. Other suitable excipients for non-aqueous compositions is Starch 1500 LM, a type with low content of moisture, Superdisintegrating substance sodium starch glycollate is used in optimal concentration 2 ÷ 4%. Because of the compai-atively low dosage of the active substance and its hygroscopic propeities it is chosen as a technological method dry mixing of the components with suitable reological properties for filling. Examples: The invention is illustrated with the following Examples. Example 1 Preparation of hard gelatin capsules, containing 50 mg of miltefosine. (Table Removed) The theoretical mass of one capsule is 190 mg. The process of mixing is carried out in diffuse mixer type "Turbula". At first the concentrate of the active substance and 50% of microcrystalline cellulose is prepared. After that are added the rest of the components and at the end talc. The finished mixer is filled in hard gelatin capsules with size 1 on capsule automate. During encapsulation the mass and disintegration of the capsules are observed periodically. Example 2 Preparation of hard gelatin capsules, containing 10 mg of miltefosine. (Table Removed) The theoretical mass of one capsule is 120 mg. Example 3 Content of capsules 50 mg of miltefosine. (Table Removed) Example 4 Content of capsules 10 mg of miltefosine. (Table Removed) The invention is not restricted to the embodiments disclosed in the description. Although it is the best mode of carrying out the invention, to keep the pharmaceutical composition as free from lactose as possible, very small amounts of lactose may be added with small deteriorating effects. After all, not more than 1% per weight, better not more than 0,5% per weight, always in relation to the whole composition, and at best no lactose at all, may be mentioned as limits in order to reach the aims of the invention. Detailed information concerning the Figs. 1 to 4: Fig.1: IHPC 80/300/10 HPC 80/300/10,2.6000 mg (Table Removed) We Claims :- 1. An essentially lactose-free stable oral pharmaceutical composition, comprising: • phospholipid derivatives in an amount from 5% to 85% by weight; • microcrystalline cellulose and/or starch 1500 LM in an amount from 15% to 95% by weight; and • lactose in an amount from 0% to 1 % by weight. 2. A pharmaceutical composition as claimed in claim 1, wherein said composition contains less than 0.5 % by weight of lactose. 3. A pharmaceutical composition as claimed in claim 2, wherein said composition is lactose-free. 4. A pharmaceutical composition as claimed in any of the preceding claims, wherein said phospholipid derivatives are alkylphosphocholines. 5. A pharmaceutical composition as claimed in claim 4, wherein said alkylphosphocholines comprise miltefosine. 6. A pharmaceutical composition as claimed in any of the preceding claims containing disintegrating excipient, glidant and lubricant. 7. A pharmaceutical composition as claimed in claim 5, wherein microcrystalline cellulose and/or starch 1500 LM are non- hygroscopic or possess low content of moisture.

Documents:

2878-delnp-2004-abstract.pdf

2878-delnp-2004-claims.pdf

2878-delnp-2004-complete specification (as filed).pdf

2878-delnp-2004-complete specification (granted).pdf

2878-delnp-2004-correspondence-others.pdf

2878-delnp-2004-correspondence-po.pdf

2878-delnp-2004-description (complete).pdf

2878-delnp-2004-drawings.pdf

2878-delnp-2004-form-1.pdf

2878-delnp-2004-form-13.pdf

2878-delnp-2004-form-18.pdf

2878-delnp-2004-form-2.pdf

2878-delnp-2004-form-3.pdf

2878-delnp-2004-form-5.pdf

2878-delnp-2004-gpa.pdf

2878-delnp-2004-pct-210.pdf

2878-delnp-2004-pct-409.pdf

2878-delnp-2004-pct-416.pdf

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