FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"MICROCRYSTALLINE CELLULOSE DEVOID MACRO-PELLET
COMPOSITIONS"
2. APPLICANT(S)
(a) NAME: TITAN LABORATORIES PVT. LTD.
(b) NATIONALITY: An Indian company incorporated under the
Companies Act, 1956.
(c) ADDRESS : 102 Titan House,
M.P.Vaidya Marg, 60 feet road, Ghatkopar - East, Mumbai - 400 077, Maharashtra, India.
3. PREAMBLE TO THE DESCRITION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of Invention:
The present invention is in field of pharmaceutical composition of Orlistat. More particularly, the invention relates to a pellet formulation for Orlistat composition which is devoid of microcrystalline cellulose.
Background of Invention:
Orlistat is a saturated derivative of a lipstatin, which in turn is a lactam derivative of leucine, whereby the unsaturated bonds are present at 4th and 7th position of the tridecane side chain. The unsaturated bonds present at 4th and 7th position are saturated by addition of 4 hydrogen atoms. As a result of addition of 4H-atoms at the 4th & 5th and 7th & 8th Carbon of the tridecane side chain. Due to addition of 4 hydrogen atoms as stated earlier, the molecule is, also at times, referred to as Tetrahydrolipstatin or THL.
Chemically, Orlistat (formula I) is [(2S)-1-[(2S, 3S)-3-hexyl-4-oxooxetan-2-yl] tridecan-2-yl] (2S)-2-formamido-4-methylpentanoate. The empirical formula of Orlistat is C29H53O5


The molecule was first disclosed in US4598089. Orlistat is currently marketed tinder brand name Xenical® by Roche, while OTC version is available as Alli® (by GSK), in USA. In India, Orlistat is generically marketed by many pharmaceutical manufacturers. The molecule is regularly prescribed for treatment of obesity.
Obesity is characterized by accumulation of excessive fat under tissue. Fats are generally considered as more efficient sources of energy. For instance, for every gram of fat that is metabolised, body yields 9 kcals of energy as compared to 4 kcals of energy which is yielded for one gram of

carbohydrate or protein metabolised. However, the biochemistry involved in metabolising fat is more complex than the biochemistry involved in metabolising carbohydrate. As a result of the complicated' metabolic pathway involved in fat metabolism, they are generally utilized as last source of energy. Therefore, till such time is arrived they are stored in body, mainly in adipose tissue.
The main and the easiest treatment for obesity is adoption of a lifestyle which encompasses diet control and physical exercises. Such a lifestyle has shown a success rate in range of 2 - 20%. This treatment can be further enhanced by using medical aids or drugs such as Orlistat.
Body fats are ingested as trigycerides. Triglycerides by themselves are not absorbed by body, they are required to be metabolised to corresponding fatty acid. This conversion is carried out by Upases, mainly pancreatic lipases.
Orlistat exerts its action by inhibiting pancreatic lipase, an enzyme that breaks down triglycerides in the intestine. The inhibition of lipase is effected by forming a covalent bond with the serine residue of the active site of gastric and pancreatic lipases, thereby disrupting the active site and resulting in inhibition of the enzyme. With this enzyme inhibited,

triglycerides from the diet are not hydrolysed into absorbable free fatty acids and are excreted undigested.
As undigested triglycerides are not absorbed, as result of which a caloric deficit is caused. This deficit may have a positive effect on weight control. At the recommended therapeutic dose of 120 mg three times a day, Orlistat inhibits dietary fat absorption by approximately 25-30%,
It is believed that for every 2 kg one loses from dieting alone, using Orlistat can help losing of additional 1 kg.
Typically, Orlistat is marketed in form of pellets which are filled in capsules. The reason for preference for pellets is that Orlistat exhibits a "picking and sticking phenomenon" while formulating in form of tablets. This drawback was overcome by pellet formulation. Orlistat pellet formulation was first disclosed in US 6004996 and the corresponding Indian Patent Applications Ns 625/CHE/2006 (F. Hoffman-La Roche). The Patent Application states that due to the low melting point of about 44°C and structural properties, Orlistat undergoes both hydrolytic and thermal degradation. The degradation is more pronounced, particularly when stored in a humid atmosphere or above 35°C in a dry atmosphere (Helvetica Chemica Acta; 73 (1990; Pages 1022-1035)) with a view of

overcoming these problem the Innovator has suggested Pellet Formulation for Orlistat.
The pellets, as disclosed in 625/CHE/2006 (published on 09/05/2008), contain Orlistat as the active ingredient and are characterized in a way that they are in the form of particles with a diameter within range of 0.25 to 2 mm. Each pellet, as claimed therein, comprises about 50% active (by weight). The Patent Application further teaches that the formulation as disclosed therein mandatorily requires presence of microcrystalline cellulose.
Another pellet formulation is subject matter of Indian Patent Application No 7393/CHENP/2009 (Dr. Reddy's Laboratories Ltd.) and corresponding US Patent Application N2 US2010/0196464. The formulation as disclosed therein comprises Orlistat powder having average particle size of less than 250um. The Patent Application further claims a pharmaceutical formulation which has an average particle size greater than 2 mm. Therefore, the formulation as disclosed and claimed in 7393/CHENP/2009 would essentially encompass a formulation that has an average formulation particle size of 2 mm or more and API particle size which is below 250 μm. On general reading of the specification of the

invention, it is apparent that the disclosed formulations essentially require presence of microcrystalline cellulose.
A controlled particle size formulation for Orlistat is disclosed in a Ranbaxy's Indian Patent Application N2 2091/DEL/2007. The said Patent Application discloses a pharmaceutical formulation which comprises Orlistat particles which have a D50 value of 120 μm and D90 value of 225 μm. The Patent Application further discloses extrusion-spheronized pellets of Orlistat. Nevertheless, the formulation as disclosed therein also apparently necessitates use of microcrystalline cellulose for preparation of formulation of the Patent Application.
62/DEL/2006 (Ranbaxy) relates to stable pharmaceutical compositions of Orlistat for treatment or prevention of obesity and hyperlipidernia. The pharmaceutical composition contains Orlistat form I, which does not convert to form II at the temperatures encountered during manufacturing of an orlistat dosage form. The pellet formulation as disclosed in this Patent Application is an extruded-spheronized formulation. The formulation as disclosed herein also uses microcrystalline cellulose for extrusion.

WO 2010/111759 (EMS SA) discloses a formulation that is, essentially, devoid of a stabilizer or any excipient which can function to stabilize the principal active ingredient or any other substance which can absorb moisture more rapidly than the active. The process as disclosed in WO '759 is developed in a manner such that the active is not exposed to any factors which could destabilize the same.
WO 2008/082373 (A2) (NOBEL ILAC SAN VE TIC A S [TR]) discloses a formulation, wherein the active lipase inhibitor is layered on a neutral pellet. The process as disclosed in WO '373 does not involve use of extrusion-spheronization technique.
WO 2011/039768 discloses an alcohol resistant formulation. The formulation as disclosed in WO '768 comprises a core comprising an active substance; a separating layer comprising at least one sugar; and a functional layer comprising at least one pharmaceutically acceptable polymer.
Apart from above mentioned formulations, most of the formulations currently available in market or described in Scientific Literature, use microcrystalline cellulose as an essential excipient. The constraint is more

pronounced wherein the process employed for pelletization is an extrusion-spheronization process.
An example of pellet formulation not using microcrystalline cellulose can be found in WO 2008/000420, wherein microcrystalline cellulose is replaced with carrageenan.
The probable reason for such widespread use of microcrystalline cellulose for extrusion-spheronization, as discussed by Otilia May Yue KOO et al in their article titled, "The Influence of Microcrystalline Cellulose Grade on Shape and Shape Distributions of Pellets Produced by Extrusion-Spheroruzation" (Chem. Pharm. Bull. 49(11) 1383-1387 (2001)), is its ability to bind water and lubricate the moist mass during the extrusion process. The bound moisture adds plasticity to the mass and thereby enables proper spheronization of the extrudate.
Even though, microcrystalline cellulose, as a spheronization aid, shows numerable advantages, the recent excavations on this subject matter have revealed that microcrystalline cellulose shows some noticeable disadvantages as well. The most proclaimed disadvantages were enumerated by Dukid-Ott, A. et al in their article titled "Production of pellets via extrusion-spheronization without the incorporation of

microcrystalline cellulose: A critical review" (Eur J Pharm Biopharm. 2009 Jan; 71(l):38-46. Epub 2008 Aug 19). Said disadvantages include a prolonged drug release of poorly soluble drugs, chemical incompatibility with specific drugs and drug adsorption onto microcrystalline cellulose fibres.
Orlistat being water insoluble drug would demonstrate the above disadvantages when formulated with microcrystalline cellulose hence directly affecting the drug release and availability.
Another disadvantage of using microcrystalline cellulose is the high costs of the material, especially as large quantities of at least 50% w/w or more are required in a formulation, which also restrict the maximum dose of drug that can be incorporated to ensure a reasonably small size of a capsule or a tablet. A number of reports have demonstrated considerable product variability because of the source ('brand') and grade variability of microcrystalline cellulose, with respect to the extrusion/spheronization process, and some cheaper brands have been suspected not to function very well.
In the view of above, it can be concluded that though microcrystalline shows innumerable advantages, when used in extrusion-spheronization it

still cannot be said to be ideal. The disadvantages as noted hereinbefore cannot be neglected.
It is noted from the disclosures hereinbefore, that though there are a number of formulations and compositions of Orlistat which are available there is need to develop certain stanch formulations and compositions which do not compel use of specific excipients for known manufacturing processes and which have set a mandate in art. Also there is a need of certain composition comprises active which has no restrictions as far as its particle size is concerned.
Therefore, the present inventors, after judicious experimentation and through literature survey, have arrived at the approach of the invention wherein microcrystalline cellulose has been not been utilized as spheronization aid.
Summary of Invention:
Accordingly, the invention provides Orlistat composition which is devoid
of microcrystalline cellulose.
In second aspect, the composition of invention is in a pellet formulation for Orlistat.

In another aspect, the final formulation judiciously comprises pellets having a particle size not less than or equal to 2 mm.
In third aspect the invention provides an immediate release pellet formulation of Orlistat.
In final aspect, the invention provides extrusion-spheronization process for manufacturing of the formulation of invention.
Detailed Description of Invention:
The invention will now be described in details with reference to preferred and optional embodiments, with a view of clearer understanding of the invention and to rule-out ambiguity, if any.
For purpose of present disclosure, singular phrases like "a", "an" and "the" also encompass plurality.
For the purpose of this invention terms "pellets" also includes "granules", "beads" or "spheroids". All the terms are used interchangeably. For the purpose of this invention terms "pellet" or "granules" or "beads" or "spheroids" refer to extruded-spheronized particles which are devoid of

microcrystalline cellulose and have an average diameter of not less than 2 mm.
For the purpose of this invention, "pelletized formulation" or "multiparticulate formulation" or "pellet formulation" refers to a formulation which essentially comprises of the pellets of the invention along with other excipients. The pelletized formulation can include, but not limited to, processed dosage forms which comprise the pellets of invention, such as, suspension or tablet or capsule or any other formulation which is designed for human consumption, by adding suitable excipients.
Pellets generally range in size, typically, between 10 - 1000 urn, though other sizes could be prepared, depending on the processing technologies employed. Micropellets are largely preferred. A similar multiparticulate dosage forms which offer similar formulation flexibility and are accepted, are rninitablets (mini-tabs).
Mini-tabs are small tablets with a diameter typically equal to or less than 3 mm that are typically filled into a capsule, or optionally, further compressed into larger tablets.

Mini-tabs combine the advantages of multiparticulate dosage forms with the established manufacturing techniques of tableting. They can be produced via direct compression and can be manufactured using conventional tableting machines with only minor equipment modifications.
Though feasible they may add up to the processing cost and affect quality especially at the compression stage. The mini-tabs being small in size may give rise to sticking and picking on the punch tips resulting in a rough and abraded surface of the tablets thus hampering the aesthetic appearance and quality of the dosage form at large.
Secondly, the multi-tip punches employed in manufacturing of such mini-tabs are liable to production hazards like punch tip breakage when operated at a high speed. The punch tip has a diameter of less than 3 mm and hence may encounter such accidental hazards when employed for manufacturing such minitablets. Also on breakage or fracture it is likely that the metal fragments of the punch material may contaminate the blend with such metal fragments which would in turn affect the product quality and production process.

The aforementioned disadvantages have been overcome by formulating Orlistat as macro pellets having a certain diameter, which is, typically, beyond the range of conventional pellets but smaller than the typical diameter of a mini-tablet.
Additionally, the larger particle size of formulation also leads to a more even packaging of particles of invention in a dosage form such as tablet or capsule.
As known to a person skilled in the art, extrusion-spheronization is best performed in presence of microcrystalline cellulose. Nevertheless, after due experimentation, it has now been found that, a similar performance of extrusion-spheronization can also be obtained by not using microcrystalline cellulose, thereby, eliminating the need to use microcrystalline cellulose therewith eliminating the disadvantages associated with use of microcrystalline cellulose. The elimination of microcrystalline cellulose also reduces overall production cost.
In view of above presented rationale, the present invention describes a composition and formulation of Orlistat pellets which overcomes the existing limits and mandates as portrayed in prior art and is economical

and processed in an easy way to give a stanch composition and formulation.
The invention, specifically, describes a novel Orlistat composition which is essentially devoid of microcrystalline cellulose.
The invention further describes a pellet formulation containing the composition of invention wheiein the diameter of individual pellets in final formulation is not less than or equal to 2 mm.
In an advantageous embodiment, the formulation of the invention is manufactured by extrusion-spheronization technique for formation of pellets. It is particularly advantageous to use extrusion-spheronization technique for manufacturing the formulation of the invention. Since extrusion-spheronization technique allows manufacture of pellets which vary over a very narrow range with regards to individual particle diameter.
In an embodiment the formulation of invention contains therapeutically effective amount of Orlistat along with such an amount of starch which is required to obtain pharmaceutically and commercially acceptable pellets.

In additional embodiment, the composition of the invention further contains pharmaceutically acceptable filler, preferably mannitol.
In subsequent embodiment, the composition of the invention further consists of a pharmaceutically acceptable disintegrant. The disintegrant can be selected from group consisting of, but not limited to, croscarmellose sodium, sodium starch glycolate, sodium carboxymethyl cellulose, crospovidone, alginic acid and alginates. Preferably, the disintegrant is croscarmellose sodium.
The composition further consists of a surfactant. The surfactant of the present invention is an anionic surfactant, preferably Sodium Lauryl Sulphate.
In subsequent embodiment, the formulation of invention further comprises a pharmaceutically acceptable binder and a pharmaceutically acceptable colouring agent and/or an opacifying agent.
In an optional embodiment, the formulation of invention can be further filled in hard-gelatin capsules. Alternatively, the pellets may be compressed to form tablets. Alternatively, the formulation, when in form

of pellets or granules or beads, can be administered as such or in form of suspension or powder for suspension.
In a preferred embodiment, the diluent is Starch and/or lactose or mannitol. The disintegrant is croscarmellose sodium. The surfactant is sodium lauryl sulphate. The binder is polyvinylpyrrolidone, preferably K-30 grade and colouring agent is titanium dioxide.
In a most preferred embodiment, the formulation of invention is characterized in that the formulation is devoid of microcrystalline cellulose and has an average particle diameter of not less than or equal to 2mm. The formulation of invention is further characterized in that the formulation is in form of pellets. The pellets of the invention are manufactured by extrusion-spheronization technique. The invention is preferably independent of API particle size.
In further most preferred embodiment, the formulation of invention consists of around 50% w/w Orlistat. The formulation further comprises starch alongwith lactose or mannitol as diluent, croscarmellose sodium optionally together with crospovidone, as disintegrant, polyvinylpyrrolidone as binder. The pharmaceutical composition further comprises an anionic surfactant which is Sodium Lauryl Sulphate.

In an embodiment, the process for manufacturing of the formulation of invention comprises of sifting and mixing Orlistat with the pharmaceutical excipients. The dry blend thus obtained is wet mixed, to obtain a wet mass. The wet granulated mass thus obtained is extruded through suitable screen and subsequently spheronized. The spheronized pellets are air dried and sized to desired particle size. The extrusion-spheronization process as employed in this invention differs with respect to use of starch or it derivatives or combinations as spheronization aid.
The invention will now be illustrated with help of example. The aforementioned embodiments and below mentioned examples are for illustrative purpose and are not meant to limit the scope of the invention. Various modifications of aforementioned embodiments and below mentioned examples are readily apparent to a person skilled in the art. All such modifications may be construed to fall within the scope and limit of this invention as defined by the appended claims.
EXAMPLES:
Example 1: Orlistat Immediate Release Pellets 50% w/w

Ingredient
Rationale
Orlistat Active Pharmaceutical Ingredient
Starch Diluent/Spheronization Aid
Lactose Diluent
Mannitol Filler
Croscarmellose sodium Disintegrant
Sodium Lauryl Sulphate Surfactant
PVP K-30 Binder
Titanium Dioxide Colouring agent/ pigment
Purified water* Solvent for granulation
* Not Present in Finished Formulation.
The formulation as described in Table 1 is manufactured by the process comprising:
1. Sifting Orlistat through specified sieve;
2. sifting starch, lactose, mannitol, croscarmellose sodium, sodium lauryl sulphate, polyvinylpyrrolidone K-30 and titanium dioxide through specified sieve followed by mixing with the sifted Orlistat of step 1;
3. mixing the blend of step 2 in a planetary mixer;
4. granulating the dry blend of step 3 with water;
5. extruding the wet mass of step 4 through specified screen;
6. spheronizing the extrudate of step 5 on specified chequered plate to get desired particle size of pellets;

7. air drying the spheronized pellets of step 6 to achieve LOD not more than 2.0%, and
8. sizing the dried pellets through specified sieve.
Example 2: Orlistat Immediate Release Pellet formulation 50% w/w

Name of ingredients Rationale
Orlistat Active Pharmaceutical ingredient
Starlac Diluent
Mannitol Filler
Croscarmellose sodium Disintegrant
Sodium Lauryl Sulphate Surfactant
PVPK30 Binder
Titanium Dioxide Coloring agent/pigment
Purified water* Solvent for granulation
TOTAL —
Procedure;
1. Passing the API (Orlistat) through specified sieve;
2. Passing through same sieve Starlac, Mannitol, Croscarmellose sodium, SLS, PVP K 30, Titanium Dioxide and Mixing well;

3. transferring the ingredients of step (1) and (2) into the PLM and dry mixing;
4. granulating the blend of step (3) in PLM using water;
5. extruding the wet mass for step (4) through specified screen;
6. spheronizing the mass of step (5) to get the desired particle size through 2mm checkered plate;
7. drying the spheronized pellets of step (6) in tray drier only by air drying (Limit: LOD NMT 2.0% at 40°C for 5mins.)
8. sifting the dried granules through sieve #08-#10 for sizing of pellets.
Example 3: Orlistat Immediate Release Pellets

Sr. No. Ingredients Function
1 Orlistat API
2 Mannitol Diluent
3 Croscarmellose Sodium Disintegrating Agent
4 Crospovidone XL Disintegrating Agent
5 Povidone K-30 Binder
6 Sodium Lauryl Sulphate Surfactant
7 IPA Solvent
1. Dissolving Orlistat in IP A;
2. passing all the excipients through specified sieve and mixing it for 5 min;

3. granulating the dry mixture of step (2) with drug solution of step
(1);
4. extruding the wet mass of step (3) through specified screen;
5. spheronizing the extrudes of step (4) to form pellets;
6. sieving the pellets of step (5) through #10;
7. air drying the pellets retained on #10 in a dryer. (Water content NMT 3.0%w/w)

We Claim,
1. A pharmaceutical composition for Orlistat characterized by having average particle size of individual pellets of not less than or equal to 2mm, wherein the composition is devoid of microcrystalline cellulose
2. The pharmaceutical composition according to Claim 2 characterized in that the formulation is manufactured by extrusion-spheronization technique.
3. The pharmaceutical composition as claimed in any of the preceding claims, wherein the formulation comprises starch.
4. The pharmaceutical composition of Claim 5 comprises lactose as diluent, mannitol as filler, croscarmellose sodium as disintegrant, polyvinylpyrrolidone as binder.
5. The pharmaceutical composition as claimed in Claim 6 further comprises an anionic surfactant.

6. The pharmaceutical composition as claimed in Claim 7, wherein the anionic surfactant is Sodium Lauryl Sulphate.
7. The pharmaceutical composition of any or preceding claims is characterized in that the formulation is independent of API particle size.
8. The pharmaceutical composition as claimed in Claims 2 and 8, wherein said formulation is optionally compressed in form of tablets or filled into capsules or sachets.
9. The pharmaceutical composition according to any of the preceding claims is manufactured by a process which comprises steps of:
a. sifting the ingredients through specified sieves;
b. mixing the sifted ingredients of step (a) in a planetary mixer to get a
uniform blend;
c. granulating the blend of step (b) in the Planetary mixer;
d. extruding the mass of step (c) through 1 mm screen;
e. spheronizing the mass of step (d) to get desired particle size and air
dried, and
f. sizing the dried pellets of step (e) to desired size.

10. The process as claimed in Claim 10, wherein said process further comprises compressing said pellets in form of tablets or further filling into capsules.