FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition of sirolimus and process for preparation thereof.
BACKGROUND OF THE INVENTION
Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus which was discovered first for its properties as an antifungal agent. It adversely affects the growth of fungi such as Candida albicans and Microsporum gypseum. Rapamycin, its preparation and its antibiotic activity were described in US 3,929,992. In 1977 Martel, R. R. et al. reported immunosuppressive properties of rapamycin against experimental allergic encephalitis and adjuvant arthritis in the Canadian Journal of Physiological Pharmacology, 55, 48-51 (1977) In 1989, Calne, R. Y. et al. in Lancet, 1989, no. 2, p. 227 and Morris, R. E. and Meiser, B. M in Medicinal Science Research, 1989, No. 17, P. 609-10, separately reported the effectiveness of rapamycin in inhibiting rejection in vivo in allograft transplantation. US 5,100,899 discloses the use of Rapamycin to inhibit transplantation rejection in mammals.
Its poor oil and water solubility, poses a significant problems in formulating the drug into suitable dosage form. In addition, it has been reported that compositions of Sirolimus with conventional excipients show unpredictable dissolution rates, irregular bioavailability profiles, as well stability problems. Currently, Sirolimus is available in two dosage forms namely tablet and
oral solution.
US 5,989,591 and US 5,985,325 disclose a solid dosage unit of rapamycin comprising a core, which is over coated with rapamycin, and a sugar coat containing one or more surface modifying agents, one or more sugars and optionally one or more binders.
US 5,145,684 discloses a nanoparticulate composition comprising particles consisting of a poorly soluble drug having adsorbed onto the surface thereof a non-crosslinked surface stabilizer wherein effective average particle size of drug substance is less than about 400 nm
SUMMARY OF THE INVENTION
Now, we have developed an alternate pharmaceutical composition for an oral administration comprising sirolimus and process for preparation thereof.
Hence, according to one of the aspects, there is provided a pharmaceutical composition of sirolimus comprising an inert core and sugar overcoat, wherein said sugar overcoat comprises
a) sirolimus;

b) poloxamer; and
c) a binder selected from the group consisting of hydroxypropylcellulose or hydroxypropyl methyl cellulose or mixture thereof;
and said poloxamer is other than poloxamer 188.
In another aspect, there is provided a pharmaceutical composition of sirolimus comprising an inert core and sugar overcoat, wherein said sugar overcoat comprises
a) about 1-5% w/w of sirolimus;
a) about 0.05-5% w/w poloxamer; and
b) about 0.05-4% w/w of a binder selected from the group consisting of hydroxypropylcellulose or hydroxypropyl methyl cellulose or mixture thereof;
and said poloxamer is other than poloxamer 188.
In another aspect, there is provided a pharmaceutical composition of sirolimus comprising an inert core and sugar overcoat, wherein said sugar overcoat comprises
a) sirolimus;
b) poloxamer;
c) microcrystalline cellulose; and
d) a binder selected from the group consisting of hydroxypropylcellulose or hydroxypropyl methyl cellulose or mixture thereof;
and said poloxamer is other than poloxamer 188.
In another aspect, there is provided a pharmaceutical composition of sirolimus comprising an inert core and sugar overcoat, wherein said sugar overcoat comprises
a) about 1-5% w/w of sirolimus;
b) about 0.05-5% w/w poloxamer;
c) about 0.05-3% w/w of microcrystalline cellulose; and
b) about 0.05-4% w/w of a binder selected from the group consisting of hydroxypropylcellulose or hydroxypropyl methyl cellulose or mixture thereof;
and said poloxamer is other than poloxamer 188.
In another aspect, there is provided a pharmaceutical composition of sirolimus comprising an
inert core and sugar overcoat, wherein said sugar overcoat comprises
a) about 1-5% w/w of sirolimus;
b) about 0.05-5% w/w poloxamer;
c) about 0.05-0.3% w/w of microcrystalline cellulose;
d) about 0.05-4% w/w of a binder selected from the group consisting of hydroxypropylcellulose or hydroxypropyl methyl cellulose or mixture thereof; and
e) about 0.02-2% w/w of antioxidant
and said poloxamer is other than poloxamer 188.
In another aspect, there is provided a process for preparation of pharmaceutical composition of Sirolimus comprising the steps of:
a) Preparation of an inert core;
b) Optionally, seal coating the inert core of step a);
c) Optionally, sub coating the inert core of step b);
d) Preparation of dispersion of sirolimus, poloxamer, microcrystalline cellulose, a binder selected from the group consisting of hydroxypropyl methylcellulose or hydroxypropyl cellulose or mixtures thereof and optionally one or more pharmaceutically acceptable excipients in a suitable vehicle;
e) Coating inert core of step a) or step b) or step c) with sirolimus dispersion of step d); and
f) Optionally, further coating said drug coated cores to obtain desired pharmaceutical composition;
wherein said poloxamer is other than poloxamer 188.
In another aspect, there is provided a method of treatment of organ or tissue transplant rejection, autoimmune disease, inflammatory conditions, or multi-drug resistance, the method comprising: orally administering to a subject a pharmaceutical composition of sirolimus comprising an inert core and sugar overcoat, wherein said sugar overcoat comprises
a) sirolimus;
b) poloxamer;
c) microcrystalline cellulose; and
d) a binder selected from the group consisting of hydroxypropylcellulose or hydroxypropyl methylcellulose or mixture thereof;
and said poloxamer is other than poloxamer 188.
DETAILED DESCRIPTION
"Sirolimus" as employed herein is intended to include amorphous or crystalline form of the drug The crystalline form may include polymorph form I or II or a mixture thereof.
Inert core" as used herein includes inert tablet core or inert beads or spheres.
Pharmaceutical composition may be in the form of tablet comprising an inert core and coating of sirolimus dispersion or it may be in the form of capsule comprising coated beads or spheres or granules.
Inert tablet core may be prepared by blending pharmaceutical acceptable excipients such as diluents, glidants and compressing into a suitable size tablet.
Inert tablet core may be further coated with sugar dispersion/solution. Sugar coating may be in the form of seal coating, sub coating, syrup coating and the like.
Inert core is coated with a sugar overcoat comprising sirolimus, poloxamer and hydroxypropyl methylcellulose. Poloxamer act as surfactant and enhances the solubility of poorly soluble drug, sirolimus. Hydroxypropyl methylcellulose is used as a binder in the sugar overcoat.
Poloxamer (polyoxyethylene-polyoxypropylene copolymers) is a crystalline or semi-crystalline material that generally has a molecular weight ranging from about 2000 to about 15,000 daltons. Suitable poloxamers are sold under the trade names PLURONIC and LUTROL, both available from BASF Corporation. Some of the commercially marketed grades of poloxamers other than poloxamer 188 include poloxamer 237 (PLURONIC F87), poloxamer 338 (PLURONIC F108), poloxamer 407 (PLURONIC F127). The amount of poloxamer present in the present invention is about 0.05-5 percent by weight of the sugar overcoat, in particular about 0.5-2% by weight of the sugar overcoat. It may be used with other surfactant or surface modifiers selected the group consisting of sorbitan esters, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone, polyethoxylated fatty acids, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4-150 mono dilaurate and the like.
Binder is selected from the group consisting of hydroxypropyl methylcellulose or hydroxy propyl
cellulose. Hydroxypropyl methylcellulose polymers are hydrophilic in nature. It may be used in different viscosity grades such as those available under the brand name Methocel™ available from Dow Chemical Co. and Metolose™ from Shin Etsu Ltd. Examples of hydroxypropyl methylcellulose polymers include those available under the brand names Methocel™ E5, Methocel™ E-15 LV and Methocel™ E50 LV.
Hydroxypropylcellulose polymers are hydrophilic in nature. Examples of hydroxypropyl cellulose include those available under the brand names of Klucel GF, Klucel JF, Klucel LFand Klucel EF.
The amount of hydroxypropyl methylcellulose or hydroxy propyl cellulose present in the present invention is about 0.05 - 4 percent by weight of sugar overcoat, in particular 0.2-1 5% w/w.
Microcrystalline cellulose is added in the composition as reinforcing agent. It controls the rate of release of Sirolimus from the sugar coating. The amount of microcrystalline cellulose may vary from about 0.05-3%, in particular, about 0.05-0.3% w/w based on the weight of sugar overcoat.
The above pharmaceutical composition of sirolimus may contain sirolimus particles having d90 value of about 2-10 urn and d5o value of about 0.5-4 urn.
The known particle size analysis methods can be used for determining the particle size, for example particle size measurement using light, like light-scattering methods, in particular Malvern mastersizer.
Micronization may be carried out using dry milling technique or supercritical fluid technique may be utilized for particle size reduction.
Seal coating is used to prevent moisture penetration into the tablet core and thus prevents the tablet core from disintegrating during the over coating process. Seal coating may comprise shellac, oleic acid, propylene glycol, talc, polyethylene glycol or mixture thereof.
Sub coating as used herein is used to round the edges and build up the tablet size. Sub coating
in addition to sugar may comprise other excipients selected from the group consisting of starch, talc, calcium carbonate, calcium sulfate or mixture thereof.
Other than sugar coating, tablet may further comprise film coating include functional or non functional layer. The coating may be selected from amongst one or more of those suitable coating materials known in the art. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension. The tablets may be polished using carnauba wax or any other waxy material, however, the amount of waxy substance selected should be optimum so that release of drug from the polymer is not altered due to presence of these excipients. The amount of polishing material may vary from 0.01-1.00 mg/tab, in particular, 0.01-0.04 mg/tab.
Coating is done using any conventional coating technique known in the art, such as spray coating in a conventional coating pan orfluidized bed processor; or dip coating.
The term "pharmaceutically acceptable excipients" as used herein include, sugars, diluents, lubricant/glidants, disintegrating agents, antioxidants and coloring agents.
Sugars may be used to prepare sugar barrier coat or over coat or drug coat wherein the drug coat comprises dispersion of the sirolimus and sugars or one or more pharmaceutical acceptable excipients. Sugar may include lactose, mannitol, sorbitol, sucrose and mixtures thereof.
The term "diluents" as used herein includes calcium carbonate, calcium phosphate-dibasic. calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, sucrose and mixtures thereof.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, and mixtures thereof.
Disintegrating agents may be selected from starches or modified starches such as starch, modified starch, croscarmellose sodium, crospovidone and sodium starch glycolate.
The composition may further comprise antioxidant, to protect the drug from oxidative degradation. Antioxidants may be selected from group consisting of ascorbic acid, sodium pyrosulphite, glutathion or sorbic acid, tocopherol and the like, in particular tocopherol E-acetate. The amount of antioxidant present in the present invention is about 0.02-2%, in particular 0.05%-0.5% w/w of sugar overcoat.
Coloring agent may be selected from FDA approved colorants and the examples are Iron oxide Opalux yellow, Lake of Tartrazine, Allura red, Lake of Quinoline yellow, Lake of Erythrosine.
The vehicle used to prepare the dispersion may be selected from water or its mixture with other
organic solvent such as ethanol, methanol, isopropyl alcohol and ether.
According to one of the embodiment, there is provided a process for the preparation of sugar over coated tablet, comprising the steps of:
i) Blending and sifting pharmaceutically acceptable excipients;
ii) Optionally, granulating blend of step i);
iii) Compressing blend of step i) or granules of step ii) into a suitable size tablet to obtain an inert core ;
iv) Dissolving/dispersing sirolimus, poloxamer, microcrystalline cellulose, hydroxypropyl methylcellulose or hydroxypropyl cellulose and optionally one or more pharmaceutically acceptable ingredients in a suitable vehicle;
v) Coating the dispersion of sirolimus of step iv) onto the inert core of step iii);
vi) Optionally, further coating drug coated core of step v).
According to another embodiment, there is provided a process for the preparation of sugar over coated tablet, comprising the steps of:
i) Blending and compressing pharmaceutically acceptable excipients to obtain an inert core;
ii) Coating a dispersion or solution of shellac and optionally one or more pharmaceutically acceptable excipients onto the inert core of step i) to obtain seal coated tablet;
iii) Coating a dispersion or solution of sucrose and optionally one or more pharmaceutically acceptable excipients onto the seal coated tablet of step ii) to obtain sub coated tablet;
iv) Coating a dispersion or solution of sucrose, binder and optionally one or more pharmaceutically acceptable excipients onto the coated tablet of step iii) to obtain sugar barrier coated tablet;
v) Dissolving/dispersing sirolimus, poloxamer, microcrystalline cellulose, hydroxypropyl methylcellulose or hydroxypropyl cellulose and optionally one or more pharmaceutically acceptable ingredients in a suitable vehicle;
vi) Coating the dispersion / solution of step v) onto the inert coated tablet of step iv);
vii) Coating a dispersion of antioxidant, sucrose and optionally one or more pharmaceutically acceptable excipients in a suitable solvent onto the drug coated tablet of step vi)
viii) Optionally, further film coating the tablet of step vii)
According to another embodiment, there is provided a process for the preparation of sugar over
coated tablet, comprising the steps of:
i) Dissolving/dispersing sirolimus, poloxamer, microcrystalline cellulose, hydroxypropyl methylcellulose or hydroxypropyl cellulose and optionally one or more pharmaceutically acceptable ingredients in a suitable vehicle;
ii) Wet milling the dispersion of step i) into a desired particle size range;
iii) Coating the milled dispersion of sirolimus of step ii) onto an inert core); and
iv) Optionally, coating drug coated core of step iii).
The solvent used for granulation and coating may be selected from water, alcohols like methyl alcohol, ethyl alcohol or isopropyl alcohol, acetone, and mixture thereof.
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of this invention in any way.
EXAMPLES
EXAMPLE 1

(Table Removed)* Sub Coat contains Sucrose-65%, Calcium Sulfate-22%, MCC-8%, Macrogol/PEG-20000-2% and Titanium dioxide-2%.
** contains DL-alpha tocopherol acetate (50%) starch, fish gelatin, sugar, Silicon-di- oxide (E
551)
Procedure:
A. Preparation of Inert core
i) Lactose, polyethylene glycol, talc and magnesium stearate were blended together and compressed into a suitable tablet;
B. Seal coatingi) Pharmaceutical glaze was diluted to 25%w/w solution using absolute alcohol;


ii) Inert tablets of step A were coated with solution of step i);
C. Sub coating
i) Sub coat was dispersed in water to obtain a 70 %w/w of sub coat suspension; ii) The suspension of step i) was used to coat the coated tablets of step B;
D. Sugar barrier coat
i) Sucrose, tocopherol and HPMC were dispersed in water;
ii) Dispersion of step i) was coated over the coated tablet of step C;
E. Drug layering
i) Poloxamer 407 was dissolved in water;
ii) Hydroxypropyl methylcellulose was dissolved in solution of step i);
iii) Sugar was added in solution of step ii) under stirring;
iv) Microcrystalline cellulose was dispersed in syrup of step iii) under stirring;
v) Sirolimus was dispersed in syrup of step iv) under stirring;
vi) Tocopherol was dispersed in dispersion of step v) under stirring;
vii) The resulting dispersion was coated onto the sugar barrier coated tablet of step D;
F. Over coat
i) Sucrose, tocopherol and HPMC were dispersed in water;
ii) Dispersion of step i) was coated over the coated tablet of step E; H. Color coat
i) Opalux yellow was dispersed in water;
ii) Dispersion of step i) was coated onto the over coated tablet of step F; I. Polishing
i) Carnauba wax was dispersed in methanol;
ii) Dispersion of step i) was coated over the color coated tablet of step H. BIOEQUIVALENCE STUDY
Bioavailability study of the Sirolimus tablet (2mg) tablet of example 1 was carried out on healthy male volunteers (n=7) taking Rapamune (2mg) produced by Wyeth Pharms as the reference, the results of which are represented in Table 1 and 2. The objective of this study was to show that a formulation of example 1 provides an activity and safety profile that is similar to one obtained with an equivalent product in the market.
11

Single dose (2mg) two way crossover and open randomized study was designed as, two
treatment, two period, two sequence study was used for comparative bioavailability of sirolimus
tablet of example 1 and rapamune tablet (2 mg) of Wyeth Pharms, under fasting and fed
conditions.
Table 1: Comparative pharmacokinetic parameters for the sirolimus (Example 2) and
Rapamune tablet under fed conditions.
(Table Removed)
Table 2: Comparative pharmacokinetic parameters for the sirolimus (Example 2) and Rapamune tablet under fasting conditions.

(Table Removed)
AUC0 -x for sirolimus tablet was within 80-125% (at 90% Confidence Interval) as shown in Table 1 and 2. The results show that sirolimus 2 mg tablets prepared as per the examples described herein have bioavailability comparable to the reference product, rapamune tablet 2 mg of Wyeth Pharmaceutical, USA.EXAMPLE 2

(Table Removed)
* Sub Coat contains Sucrose-65%, Calcium Sulfate-22%, MCC-8%, Macrogol/PEG-20000-2% and Titanium dioxide-2%.
Procedure:
A. Preparation of Inert core
i) Lactose, polyethylene glycol, talc and magnesium stearate were blended together and compressed into a suitable tablet;
B. Seal coating
i) Pharmaceutical glaze was diluted to 25%w/w solution using absolute alcohol; ii) Inert tablets of step A were coated with solution of step i);
C. Sub coating
i) Sub coat was dispersed in water to obtain a 70 %w/w of sub coat suspension; ii) The suspension of step i) was used to coat the coated tablets of step B;
D. Sugar barrier coat
iii) Sucrose, tocopherol and HPMC were dispersed in water;
iv) Dispersion of step i) was coated over the coated tablet of step C;
E. Drug layering
i) Poloxamer 407 was dissolved in part of water;
ii) Sirolimus was dispersed in solution of step i) under stirring;
iii) Hydroxypropyl methylcellulose was dissolved in another part of water;
iv) Vitamin E was loaded over sucrose using low shear mixture;
v) Vitamin E loaded sucrose was dispersed in solution of step iii);
vi) Dispersion of step ii) was added into dispersion of step v);
vii) Microcrystailine cellulose was dispersed in dispersion of step vi) under stirring;
viii)The resulting dispersion (d90 - 5.46 and d50 - 2.12) was coated onto the sugar barrier coated tablet of step D;
F. Over coat
i) Sucrose, tocopherol and HPMC were dispersed in water;
ii) Dispersion of step i) was coated over the coated tablet of step E; H. Color coat
i) Opalux yellow was dispersed in water;
ii) Dispersion of step i) was coated onto the over coated tablet of step F; I. Polishing
i) Carnauba wax was dispersed in methanolli) Dispersion of step i) was coated over the color coated tablet of step H.
EXAMPLE 3

(Table Removed)
* Sub Coat contains Sucrose-65%, Calcium Sulfate-22%, MCC-8%, Macrogol/PEG-20000~2% and Titanium dioxide-2%.
Procedure as given in Example 2 was followed for the preparation of composition as given in Example 3.

WE CLAIM:
1. A pharmaceutical composition of sirolimus comprising an inert core and sugar overcoat,
wherein said sugar overcoat comprises
a) sirolimus;
b) poloxamer;
c) microcrystalline cellulose; and
d) a binder selected from the group consisting of hydroxypropylcellulose or hydroxypropyl methylcellulose or mixture thereof;
and said poloxamer is other than poloxamer 188.
2. The pharmaceutical composition according to claim 1 wherein the poloxamer is present in the amount of about 0.05-5% w/w.
3. The pharmaceutical composition according to claim 1 wherein the poloxamer is selected from the group comprising poloxamer 237, poloxamer 338 or poloxamer 407.
4. The pharmaceutical composition according to claim 1 wherein the binder is present in the amount of about 0.05-4% w/w.
5. The pharmaceutical composition according to claim 1 wherein the microcrystalline cellulose is present in the amount of about 0.05-3% w/w.

6. The pharmaceutical composition according to claim 5 wherein the microcrystalline cellulose is present in the amount of about 0.05-0.3% w/w.
7. The pharmaceutical composition according to claim 1 wherein the Sirolimus have particle size with d90 value of about 2-10 um.
8. The pharmaceutical composition according to claim 1 may further comprise an antioxidant.
9. The pharmaceutical composition according to claim 1 wherein the pharmaceutical composition is a tablet or a capsule.
10 The pharmaceutical composition according to claim 9 wherein the tablet comprises an inert tablet core and a sugar overcoat.
11. The pharmaceutical composition according to claim 1 wherein the pharmaceutical
composition is prepared by a process comprising the steps of:
a) Preparation of an inert core;
b) Optionally, seal coating the inert core of step a);

c) Optionally, sub coating the inert core of step b); and
d) Preparation of a dispersion of Sirolimus, poloxamer, microcrystalline cellulose, binder
or mixture thereof and optionally one or more pharmaceutically acceptable excipients in a suitable vehicle;
e) Coating the inert core of step a) or step b) or step c) with the sirolimus dispersion of
step d);
f) Optionally, further coating said drug coated cores to obtain the desired pharmaceutical
composition.
12. The pharmaceutical composition according to claim 11 wherein the pharmaceutically
acceptable excipients include sugars, diluents, lubricant/glidant, disintegrating agent, and
coloring agents.
13. The pharmaceutical composition as described and exemplified herein.