WO2003090757A1

WO2003090757A1 - Pharmaceutical compositions of phospholipid derivatives

Info

Publication number: WO2003090757A1
Application number: PCT/IB2002/002786
Authority: WO
Inventors: Rudolf Perl
Original assignee: Rudolf Perl
Priority date: 2002-04-26
Filing date: 2002-04-26
Publication date: 2003-11-06
Also published as: BR0215680A; AU2002346284A1

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.

Description

PHARMACEUTICAL COMPOSITIONS OF PHOSPHOLIPID DERIVATIVES

The invention relates to oral dosage forms containing phospholipid derivatives.

B ackground 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), α-phosphatidyl choline, α-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 carried 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 compositions 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 82 l^e 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.1 :

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.

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 prepared 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 F₂s plate (Merck), with layertickness 0.25 mm. Test solution - 100 mg are dissolved in 4 ml of Chloroform. 20 μl 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 R_f 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 (Nivapur type 112) with low content of moisture (< 3%). 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, < 6%, exhibiting properties of binding, disintegrating, improving the fiowability and lubricating substance. Superdisintegrating substance sodium starch glycollate is used in optimal concentration

2 ÷ 4%.

Because of the comparatively low dosage of the active substance and its hygroscopic properties 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.

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.

The theoretical mass of one capsule is 120 mg.

Example 3

Content of capsules 50 mg of miltefosine.

Example 4

Content of capsules 10 mg of miltefosine.

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:

Fi d: LHPC 80/300/10

HPC 80/300/10, 2.6000 mg

Fig. 1/Tabl

Integral -355.21 mJ normalized -136.62 Jg^Λ-l Onset 82.00 °C

Peak Height 2.03 Wg^Λ-l

Peak 97.49 °C

Extrapol. Peak 95.42 °C Endset 101.28 °C

Peak Width 8.12 °C

Left Limit 82.00 °C

Right Limit 123.57 °C

Left bl Limit 82.00 °C Rigth bl Limit 123.57 °C

Heating Rate 10.00 °Cmin^Λ-l

Baseline Type line

Result Mode Sample Temp

Left Area 58.79 % Rigfh Area 41.21 %

Fig. 1/Tab2

Integral -117.83 mJ normalized -45.32 Jg^Λ-l Onset 236.25 °C

Peak Height 0.54 Wg^Λ-l

Peak 250.87 °C

Extrapol. Peak 251.57 °C

Endset 255.40 °C Peak Width 11.87 °C

Left Limit 220.15 °C

Right Limit 258.04 °C

Left bl Limit 220.15 °C

Right bl Limit 258.04 °C Heating Rate 10.00 Cmin

Baseline Type line

Result Mode Sample Temp

Left Area 83.07%

Right Area 16.93% Fig.2/Text2 Milt. : MKC1123:1 80/300/10, 20.12.2001 17:43:56 Milt. : MKC1123:1 80/300/10, 12.7000 mg

Fig.2/Tab3

Integral -652.03 mJ normalized -51.34 Jg^Λ-l

Onset 97.19 °C

Peak Height 11.22 mW

Peak 103.02 °C

Extrapol. Peak 104.43 °C Endset 110.72 °C

Peak Width 9.06 °C

Left Limit 89.22 °C

Right Limit 124.80 °C

Left bl Limit 89.22 °C Right bl Limit 124.80 °C

Heating Rate 10.00 Cmin^Λ- 1

Baseline Type line

Result Mode Sample Temp

Left Area 39.03% Right Area 60.97%

Fig.2/Tab4

Integral -256.58 mJ normalized -20.20 Jg^Λ-l Onset 248.27 °C

Peak Height 5.99 W

Peak 255.11 °C

Extrapol. Peak 255.05 °C

Endset 259.27 °C Peak Width 7.49 °C Left Limit 241.05 °C

Right Limit 261.03 °C

Left bl Limit 241.05 °C

Right bl Limit 261.03 °C

Heating Rate 10.00 Cmin

Baseline Type line

Result Mode Sample Temp

Left Area 66.42 %

Right Area 33.58 %

Fig. 3:

Fig.3/Text3 Milt. : Lact (s.d.) 3:1 80/300/10, 12.12.2001 15:52:14 Milt. : Lact (s.d.) 3:1 80/300/10, 12.2000 mg

Fig.3/Tab5

Integral -514.42 mJ normalized -42.17 Jg^Λ-l

Onset 93.47 °C

Peak Height 8.36 mW

Peak 102.34 °C

Extrapol. Peak 103.12 °C Endset 108.52 °C

Peak Width 9.08 °C

Left Limit 86.13 °C

Right Limit 119.34 °C

Left bl Limit 86.13 °C Right bl Limit 119.34 °C

Heating Rate 10.00 CminM

Baseline Type line

Result Mode Sample Temp

Left Area 52.43% Right Area 47.57% Fig.3/Tab6

Integral -510.91 mJ normalized -41.88 Jg^Λ- 1 Onset 144.43 °C

Peak Height 9.56 mW

Peak 149.25 °C

Extrapol. Peak 148.97 °C

Endset 156.81 °C Peak Width 7.23 °C

Left Limit 130.01 °C

Right Limit 168.28 °C

Left bl Limit 130.01 °C

Right bl Limit 168.28 °C Heating Rate 10.00 CminM

Baseline Type line

Result Mode Sample Temp

Left Area 47.12 %

Right Area 52.88 %

Fig.3/Tab7

Integral -305.91 mJ normalized -25.07 JgM

Onset 209.84 °C

Peak Height 4.38 mW

Peak 214.53 °C

Extrapol. Peak 214.54 °C Endset 219.02 °C

Peak Width 5.52 °C

Left Limit 199.64 °C

Right Limit 242.19 °C

Left bl Limit 199.64 °C Right bl Limit 242.19 °C Heating Rate 10.00 CminM

Baseline Type line

Result Mode Sample Temp

Left Area 14.40 % Right Area 85.60 %

Fjg

Fig.4/Text4

Milt. : Starch 1500 3:1 80/300/10, 20.12.2001 16:33:13 Milt. : Starch 1500 3:1 80/300/10, 13.8000 mg

Fig.4/Tab8

Integral -489.96 mJ normalized -35.50 Jg^Λ- 1

Onset 99.51 °C

Peak Height 10.72 mW Peak 104.19 °C

Extrapol. Peak 104.32 °C

Endset 109.39 °C

Peak Width 6.13 °C

Left Limit 85.71 °C Right Limit 126.63 °C

Left bl Limit 85.71 °C

Right bl Limit 126.63 °C

Heating Rate 10.00 CminM

Baseline Type line Result Mode Sample Temp

Left Area 46.23%

Right Area 53.77% Fig.4/Tab9

Integral -95.00 mJ normalized -6.88 JgM Onset 245.43 °C

Peak Height 2.13 mW

Peak 251.34 °C

Extrapol. Peak 251.67 °C

Endset 257.93 °C Peak Width 7.79 °C

Left Limit 242.38 °C

Right Limit 261.08 °C

Left bl Limit 242.38 °C

Right bl Limit 261.08 °C Heating Rate 10.00 CminM

Baseline Type line

Result Mode Sample Temp

Left Area 47.05 %

Right Area 52.95 %

Claims

Claims:

1. An oral pharmaceutical composition, which contains phopspholipid derivatives and at least a nonreactive excipient (filler), characterized in that it contains not more than 1 % per weight of lactose.

2. A stable oral pharmaceutical composition as in claim 1, characterized in that it contains not more than 0,5 % per weight of lactose.

3. A stable oral pharmaceutical composition as in claim 2, characterized in that it is essentially lactose-free.

4. A stable oral pharmaceutical composition as in any of the preceeding claims, characterized in that the phospholipid derivatives are alkylphosphocholines.

5. A stable oral pharmaceutical composition as in any of the preceeding claims, wherein the alkylphosphocholine is miltefosine.

6. A stable oral pharmaceutical composition as in any of the preceeding claims, characterized in that it contains in addition disintegrating excipient, glidant and lubricant.

7. Stable hard dosage form acording to any of the preceeding claims, which contains 5% to 85% miltefosine and accordingly 95% to 15% acceptable excipients, but is essentially lactose- free.

8. Pharmaceutical composition according to claim 5, in which the excipients are non- hygroscopic or with low content of moisture.

9. Pharmaceutical composition according to any of the preceeding claims, characterized in that it contains microcrystalline cellulose or starch 1500 LM.