FORM 2
i
The Patents Act 1970 Complete Specifications Section. 10
A process for preparation of pharmaceutical composition containg a non-steroidal anti-inflammatory drug (NSAID)
Applicant: Macleods Pharmaceuticals Ltd., an Indian company, having office at 304-310 Atlanta Arcade, Church Road, Andheri- Kurla Road, Andheri (E), Mumbai 40(j)059 Maharashtra State, India.
Inventor : DR. SHRUTI UMESH BHAT, an Indian national, C/o Macleods Pharmaceuticals Ltd.,304 - 310 Atlanta Arcade, Church Road, Andheri-Kurla Road, Andheri (E), Mumbai 400 059, Maharashtra State, India.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed :-





The present invention relates to a process for the preparation of pharmaceutical formulation containing inclusion complex of cyclodextrin and an anti-inflammatory agent.
Background of invention:-
Oral treatment of anti-inflammatory especially non-steroidal antiinflammatory drugs (NSAIDS) has the disadvantage of gastro-intestinal side effects, particularly local gastric irritation. Contact between the NSAID and the mucosa is believed to constitute an important factor in the pathogenesis of gastric irritation. (Bianchi P.G. et al, Alimentary Pharmacology and Therapeutics 1987,1, 5405-5475).
Commercial preparations of NSAID's for oral administration include enteric coated tablets which release the drug in the duodenum so as to avoid local gastric irritation. This however has the disadvantage that peak plasma levels of the drug are reached between one to four hours after administration of the enteric coated tablets.
There is therefore a need for oral pharmaceutical formulation of NSAID which provides rapid absorption due to enhanced solubility in body fluids thus leading to minimized gastro intestinal irritation.


Use of cyclodextrin as a carrier for preparation of inclusion complexes with pharmaceutical^ active agents has been well-listed in literature. [Chemical Abstracts 116 (16); 158718p (1992); Int. J. Pharmaceutics 79; 289-299 (1992); J. Pharm. Pharmacology 46(6); 470-80; Pharmaceutical Research vol. 10; No. 5, p.682-86(1993); US Patent 6113943, 6113939, 6113937, 6106875, 6106864, 6051252, 5998488, 5997848, 5997848, 5985889, 5939094, 5932223, 5925739, 5922723, 5863538, 5817332, 6106738, 6071964, 6033679, 6001821, 5977158, 5843347, 5840714, 5824668, 5679573, 5538721, 5464633, 5246611, 5182270, 5137571, 5102800, 5079237, 5068227, 5068226, 5043326, 4952565, 4865976, 4851423, 4826963, 4818749, 4783331, 4584285, 4438106, 4371673, 6113943, 6113939, 6113937, 6110449, 6107343, 6107276, 6106875,6106864, 6106858,6103678, 6103517, 6100269, 6099864, 6099628,6093181, 6090611, 6087378, 6087340, 6083985, 6096345 and 6093399] Employing cyclodextrins has been known to increase drug solubility in water. 4-hydroxy-2-methyl-N-(5-methyl-2-thiazole)-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide (Meloxicam) is a NSAID, practically insoluble in water. Meloxicam is being prescribed for pain management and as an antiinflammatory agent.
The present invention relates to a process for preparation of pharmaceutical formulation of a NS AID containing inclusion complexes of cyclodextrin and an anti-inflammatory medicament such as Meloxicam.
3

Scope of invention:
The invention involves formation of a complex of NSAID or a pharmaceutically accepted salt thereof, with cyclodextrin subsequently being incorporated in the preparation of a pharmaceutical formulation.
The NSAID may be a suitable NSAID such as for example meloxicam, celecoxib, rofecoxib, nefopam, nabumetone etc. or a pharmaceutically acceptable salt thereof.
The cyclodextrin may be any suitable cyclodextrin but is preferably a beta-cyclodextrin which may be suitable for example with methyl or hydroxypropyl groups or preferably an unsubstituted beta-cyclodextrin.
The pharmaceutical composition is preferably formulated as a tablet, capsule, granules, pellets, spansules, pulvule, dermatological as well as a parenteral. Several complexation techniques such as kneading, milling and trituration as well as combination thereof may be attempted. However, ball-milling technique being preferred for complexation of cyclodextrin - NSAID. The process involves use of the NSAID complex along with binder, disintegrating agents, lubricants, levigating agent and other additives.
The formulation may or may not contain atleast one further active ingredient.


An inclusion complex for use in the process of preparation pharmaceutical composition of the invention may be prepared as follows :
1. Premixture of the required ratios of pre-screened NSAID and cyclodextrin.
2. Transfer to a ball-mill containing balls made either of porcelein or stainless steel. Ball milling the blend for a definite period of time for e.g. 2-8 hours with occasional scraping of the blend from the sides of the mill until the complex is formed.
3. Screening the complex solid through 60#.
4. Adding formulation additives such as binders, bulking agents, levigating agents, surfactants, etc. and granulating the mass to form a dough.
5. Wet screening of the above dough of step (4) through 8 mesh and drying the granules obtained at 60°C in a fluidized bed drier for 1-4 hours or in a tray drier for upto 12 hours until granules with moisture content between 2.5 - 3.0% w/w are obtained.
6. Blending the dried granules of step (5) with suitable excipients such as lubricants, disintegrants and glidants to form a suitable oral dosage form such as tablets or capsules.
7. The dough from step (4) may also be extruded through an extruder to form rods which may be then spheronized through a marumerizer to form beads or pellets.


8. The beads or pellets from step (7) may be then either encapsulated
into a hard gelatin capsule or compressed into tablets after incorporating suitable excipients such as lubricants, disintegrants and glidants.
The preferred active component of the pharmaceutical composition of the invention is an inclusion complex of Meloxicam or a pharmaceutically acceptable salt thereof and an unsubstituted beta-cyclodextrin or celecoxib or refecoxib or a pharmaceutically accepted salt thereof and an unsubstituted or substituted beta-cylcodextrin. Nefopam or a pharmaceutically accepted salt thereof or Nabumetone or a pharmaceutically active salt thereof may be incorporated as the medicament along with an unsubstituted or substituted beta-cyclodextrin.
The NSAID and cyclodextrin may be premixed at ratios between 1:1 upto 1:25, but preferably at a ratio of 1:4. The cyclodextrin being incorporated may be either substituted or unsubstituted alfa or betacyclodextrin but preferably an unsubstituted betacyclodextrin. The NSAID and cyclodextrin may be complexed either by simple addition, trituration, kneading or ball milling using stainless steel or porcelein balls, but preferabley by ball milling technique.
Several formulation additives viz. binders for example acacia, cellulose, sugars, starches, polyvinyl pyrrolidone, gelatin, pre-gelatinised starch, liquid


glucose, sorbitol, maltol etc. may be used; but preferably starch may be used. Bulking agents for example calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose, dextrose, mannitol, hydroxypropyl cellulose, lactose, starch, magnesium carbonate, magnesium oxide, sugars etc., may be incorporated but preferably starch and dicalcium phosphate may be used. Levigating agents such as water, isopropyl alcohol, water-isopropanol mixture, ethyl alcohol etc may be used, but preferably purified water may be used.
Surfactants such as sodium lauryl sulfate, polysorbate 80, poloxamer etc. may be incorporated into the formulation, but polysorbate 80 and poloxamer may be used. Disintegrants amongst crospovidone, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, starch, pre-gelatinised starch etc. may be used but preferably crospovidone and colloidal silicon dioxide are used.
The NSAID-cyclodextrin complex granules after addition of suitable fillers may be compressed into either a conventional, effervescent or a dispersible tablet or encapsulated into a hard gelatin capsule. Suitable chemical and microbial preservatives such as sodium benzoate, parahydroxy benzoates and soluble salts thereof, butylated hydroxy anisole, butylated hydroxy toluene, ascorbic acid, tocopherol, edetates, sodium chloride, propyl gallate, sodium ascorbate, sodium metabisulfite, sorbic acid, tartaric acid, citric acid,


triacetin, bronopol, sodium bicarbonate etc. may be incorporated into the formulation.
The pharmaceutical composition of cyclodextrin with meloxicam has been evaluated for the in vitro performance such as disintegration time, assay and rate of dissolution in water medium. When studied for drug availability for absorption with respect to time using the in vitro dissolution rate test the formulation containing complex, according to the invention showed a superior extent of drug solubility measured as amount of drug dissolved in water vs time when compared with commercial meloxicam tablets used as reference products. The dissolution efficiency of the formulation which is measured as the ratio of area under the dissolution rate curve at time point to the area at 100% dissolution at the same time point has been calculated. Due to enhanced dissolution, oral formulations according to the invention containing meloxicam exhibit faster availability of the drug for the purpose of absorption relative to the reference products. An increased rate of absorption is likely to reduce contact time of meloxicam and the intestinal mucosa thereby reducing the potential for gastric irritation. In addition, presentation of the drug to the gastric mucosa as complex ensures improved availability profiles in vivo for efficacious management of pain associated with inflammation.


The above specified specification can be better understood with the help of examples. However, these examples do not in any way restrict the broad scope of the invention.
Example 1
Meloxicam (7.5 g) and betacyclodextrin USP (30 g) were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added starch LP. (30 g), Dicalcium phosphate LP. (47.25 g) and polyvinyl pyrrolidone LP. (1.5 g) - (Blend A). Polysorbate 80 LP. (0.75 g) was added to Purified Water LP. (35 ml) and this mixture was added to Blend (A). Blend (A) was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for these dried granules was checked to be between 2.5 - 3% w/w. The dried granules were rasped through 20 mesh. Crospovidone LP. (3.5 g) and colloidal silicon dioxide LP. (1.5 g) were screened through 40 mesh and added to the dried granules - (Blend B). Finally talcum LP. ( 2 g) and magnesium stearate LP. (1 g) were added to Blend (B). The lubricated granules were compressed into tablets with a compression pressure at 4-5 kg/cm2. The tablets obtained at an average weight of 125 mg/tablet contained 7.5 mg of meloxicam. The tablets were evaluated for all parameters as per the general


pharmacopoeial requirements of monograph for tablet preparations as well as the rate of dissolution in water medium (Table 1).
Example 2
Meloxicam (7.5 g) and betacyclodextrin USP (30 g) were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added starch LP. (30 g), Dicalcium phosphate LP. (47.25 g) and polyvinyl pyrrolidine LP. (1.5 g) - (Blend A). Polysorbate 80 LP. (0.75 g) was added to Purified Water LP. (35 ml) and this mixture was added to Blend (A). Blend (A) was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for these dried granules was checked to be between 2.5 - 3% w/w. The dried granules were rasped through 20 mesh. Crospovidone LP. (3.5 g) and colloidal silicon dioxide LP. (1.5 g) were screened through 40 mesh and added to the granules - (Blend B). Finally talcum LP. ( 2 g) and magnesium stearate LP. (1 g) were added to the dried granules Blend (B). The lubricated granules were compressed into tablets with a compression pressure of 6-7 kg/cm . The tablets were compressed at an average weight of 250 mg/tablet which contained 15 mg of meloxicam. The tablets were evaluated for all the


parameters under general pharmacopoeial requirements for monograph for tablets as well as rate of dissolution in water medium. (Table 2)
Example 3
Meloxicam (7.5 g) and betacyclodextrin USP (30 g) were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7.0 hours to form a complex. The complex was then screened through 40 mesh. To the complex was added starch LP. (27 g), Dicalcium phosphate LP. (45 g) and polyvinyl pyrrolidone LP. (1.5 g) - Blend (A). Polysorbate 80 LP. (0.75 g) was added to purified water LP. (35 ml) and this mixture was added to Blend (A). Blend (A) was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for the dried granules was recorded to be between 2-3% w/w. The dried granules were rasped through 20 mesh. Crospovidone LP. (6.5 g) and Colloidal silicon dioxide LP. (1.5 g) were screened through 40 mesh and added to the granules - Blend (B). Finally talcum LP. (2 g), magnesium stearate LP. (1 g) and orange flavour (2.25 g) were added to the blend (B). The lubricated granules were compressed into tablets at an average weight of 125 mg/tablet containing meloxicam 7.5 mg, at a compression pressure of 4-5 kg/cm . The tablets were evaluated for all the parameters as per the pharmacopoeial requirements for tablets. In addition dispersion time and


uniformity of dispersion through 710 |_i mesh was also studied and was found to be excellent. Optionally raspberry, strawberry, cola or mixed fruit flavour may be substituted for the orange flavour, or a colour may be added to the formulation. The colour added may either be erythrosine pink, sunset yellow, tartrazine or quinoline yellow.
Example 4
Meloxicam (7.5 g) and betacyclodextrin USP (30 g) were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7.0 hours to form a complex. The complex was then screened through 40 mesh. To the complex was added starch LP. (27 g), Dicalcium phosphate LP. (45 g) and polyvinyl pyrrolidone LP. (1.5 g) - Blend (A). Polysorbate 80 LP. (0.75 g) was added to purified water LP. (35 ml) and this mixture was added to Blend (A). Blend (A) was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for the dried granules was recorded to be between 2-3% w/w. The dried granules were rasped through 20 mesh. Crospovidone LP. (6.5 g) and Colloidal silicon dioxide LP. (1.5 g) were screened through 40 mesh and added to the granules - Blend (B). Finally talcum LP. (2 g), magnesium stearate LP. (1 g) and orange flavour (2.25 g) were added to the blend (B). The lubricated granules were compressed into tablets at an average weight of 250


mg/tablet containing meloxicam 15 mg at a compression pressure of 4-5 kg/cm2. The tablets were evaluated for all the parameters as per the pharmacopoeial requirements for tablets. In addition dispersion time and uniformity of dispersion through 710 \i mesh was also studied and was found to be excellent. Optionally raspberry, strawberry, cola or mixed-fruit flavour may be substituted for orange flavour or a colour may be added to the formulation. The colour added may be either erythrosine pink, sunset yellow, tartrazine or quinoline yellow.
Example 5
Meloxicam (7.5 g) and betacyclodextrin USP (30 g) were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7.0 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added starch LP. (20 g), dicalcium phosphate (27.2 g) and polyvinyl pyrrolidone LP. (1.5 g) - Blend (A). Polysorbate 80 LP. (0.75 g) was added to purified water LP. (35 ml) and this mixture was added to Blend (A). Blend (A) was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for the dried granules was recorded to be 2.5 - 3.0% w/w. The dried granules were then rasped through 20 mesh. Citric acid LP. (anhydrous) (10 g), colloidal silicon


dioxide LP. (1.5 g), sodium bicarbonate LP. (18 g), orange flavour (2.5 g), sodium chloride LP. (0.25 g), sodium benzoate (6.8 g) and magnesium stearate LP. (0.5 g) were added to the dried granules - Blend (B). The lubricated granules were then compressed into tablets at an average weight of 125 mg/tablet with a compression pressure at 4-5 kg/cm2 under low environmental percentage relative humidity. Tablets so obtained containing 7.5 mg meloxicam, were evaluated for all parameters as per the general pharmacopoeial requirements for tablet preparations as well as the effervescent disintegration and uniformity of dispersion. The results showed excellent effervescence and dispersion uniformity. Optionally, raspberry, strawberry, cola or mixed fruit flavour may be substituted for orange flavour or a colour may be added to the formula. The colour added may be either erythrosine pink, sunset yellow, tartrazine or quinoline yellow.
Example 6
Meloxicam (7.5 g) and betacyclodextrin USP (30 g) were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7.0 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added starch LP. (20 g), dicalcium phosphate (27.2 g) and polyvinyl pyrrolidone LP. (1.5 g) - Blend (A). Polysorbate 80 LP. (0.75 g) was added to purified water LP. (35 ml) and this mixture was added to Blend (A). Blend (A) was granulated in a planetary mixer for 20 minutes.


The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for the dried granules was recorded to be 2.5 - 3.0% w/w. The granules were then raspsed through 20 mesh. Citric acid LP. (anhydrous) (10 g), colloidal silicon dioxide LP. (1.5 g), sodium bicarbonate LP. (18 g), orange flavour (2.5 g), sodium chloride LP. (0.25 g), sodium benzoate (6.8 g) and magnesium stearate LP. (0.5 g) were added to the dried granules - Blend (B). The lubricated granules were then compressed into tablets at an average weight of 250 mg/tablet with a compression pressure at 4-5 kg/cm under low environmental percentage relative humidity. Tablets so obtained containing 15 mg meloxicam were evaluated for all parameters as per the general pharmacopoeial requirements for tablet preparations as well as the effervescent disintegration and uniformity of dispersion. The results showed excellent effervescence and dispersion uniformity. Optionally, raspberry, strawberry, cola or mixed fruit flavour may be substituted for orange flavour or a colour may be added to the formula. The colour added may be either erythrosine pink, sunset yellow, tartrazine or quinoline yellow.


DISSOLUTION DATA OF MELOXICAM TABLETS
TABLE 1
NAME : MELOXICAM TABLETS
STRENGTH : 7.5 mg
DISSOLUTION MEDIUM : DISTILLED WATER

TIME(MINS) BRAND 1 BRAND 2 MELOXICAM +BCD (MACLEODS)
5 58.53% 7.26% 89.02%
10 74.16% 8.14% 88.34%
15 80.10% 9.68% 97.51%
20 81.86% 12.10% -
25 83.40% 12.98% -
30 83.62% 14.30% -
45 84.72% 17.38% -


DISSOLUTION DATA OF MELOXICAM TABLETS
TABLE 2
NAME : MELOXICAM TABLETS
STRENGTH : 15 mg
DISSOLUTION MEDIUM : DISTILLED WATER

TIME(MINS) BRAND 1 BRAND 2 BRAND 3 MELOXICAM+BCD (MACLEODS)
5 7.02% 41.59% 10.48% 76.45%
10 10.03% 64.03% 14.76% 82.14%
15 12.60% 69.66% 18.82% 86.60%
20 11.64% 71.69% 21.98% 92.74%
25 12.60% 72.93% 24.57% 93.19%
30 12.98% 74.63% 27.28% 93.19%
45 14.43% 76.77% 33.82% 94.42%


We Claim,
1. A process for the preparation of pharmaceutical composition
containing a non-steroidal anti-inflammatory agent (NSAID) comprising:
a. Mixing the required ratios of pre-screened NSAID and
cyclodextrin;
b. Milling the mixture of step (a) to a ball-mill containing balls made
either of porcelein or stainless steel. Ball milling the blend for a
definite period of time for e.g. 2-8 hours with occasional scraping
of the blend from the sides of the mill until the complex is formed;
c. Screening the complex solid through mesh;
d. Adding formulation additives such as binders, bulking
agents, levigating agents, surfactants, etc. and granulating the mass
to form a dough;
e. Wet screening of the dough of step (d) through 8 mesh and
drying the granules obtained at 60°C in a fluidized bed drier for 1-4
hours or in a tray drier for up to 12 hours until granules with
moisture content between 2.5 - 3.0% w/w are obtained;
f. Blending the dried granules of step (e) with suitable excipients
such as lubricants, disintegrants and glidants to form a suitable oral
dosage form;


Extruding dough from step (d) through an extruder to form rods
which may be then spheronized through a marumerizer to form
beads or pellets;
Encapsulating the beads or pellets from step (g) into a hard gelatin
capsule;
Compressing the beads or pellets from step (g) or granules from
step (e) into tablets after incorporating suitable excipients such as
lubricants, disintegrants and glidants;
A process for the preparation of pharmaceutical composition containing a NSAID as claimed in claim 1, where in, the antiinflammatory drug is either meloxicam or nabumetone or celecoxib or rofecoxib or nefopam or pharmaceutically acceptable salt there of.
A process for the preparation of pharmaceutical composition containing a NSAID as claimed in claims 1 or 2, where in, the cyclodextrin used is an unsubstituted beta cyclodextrin in ratios of 1:1 upto 1 :25 of drug:cyclodextrin. A process for the preparation of pharmaceutical composition containing a NSAID as claimed in claims 1 to 3 , where in, the inclusion complex may be formed using the ball milling technique.


A process for the preparation of pharmaceutical composition containing a NSAID as claimed in claims 1 to 4, where in the formulation additives incorporated may be starch, dicalcium phosphate, polyvinyl pyrolidone, polysorbate 80, poloxomer, crospovidone, colloidal silicon dioxide, talcum and magnesium stearate.
A process for the preparation of pharmaceutical composition containing a NSAID as claimed in claims 1 to 5, where in the formulation may contain flavour such as orange, strawberry, raspberry, mixed fruit or cola flavor.
A process for the preparation of pharmaceutical composition containing a NSAID as claimed in claims 1 to 6 , where in, the formulation may contain color such as erythrosine pink, sunset yellow, tartrazine or quinoline yellow. A process for the preparation of pharmaceutical composition containing a NSAID as claimed in claims 1 to 7, where in, the formulation may contain chemical and microbial preservatives such as sodium benzoates, parahydroxy benzoates and alkali metal salts there of, citric acid, sodium bicarbonate, triacetin, butylated hydroxy anisole, butylated hydroxy toluene, sodium chloride, disodium edetate and sodium metabisulfite.


9. A process for the preparation of pharmaceutical composition
containing a NSAID as claimed in claims 1 to 8, substantially as described herein before with reference to Examples 1-6.
Dated this 9th day of September 2000




ABSTRACT
"A process for preparation of pharmaceutical formulation containing inclusion complex of cyclodextrin and an anti-inflammatory agent"
The present invention relates to a process for the preparation of pharmaceutical formulation containing inclusion complex of cyclodextrin and an anti-inflammatory agent such as meloxicam. The cyclodextrin may be any suitable cyclodextrin such as substituted or unsubstituted beta cyclodextrin in ratios such as 1:1 upto 1:25 equivalents of drug : cyclodextrin. The premixed drug and cyclodextrin may be ball milled to form the complex . The complex is further mixed with formulation additives such as fillers, binder, disintegrants, lubricants, levigating agents, glidants, flavors ,colours and preservatives to form tablet.