FORM 2
THE PATENTS ACT 1970
(39 of 1970)
The Patents [Amendment] Rules, 2006 COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION

Lactose Based Coatings For Pharmaceutical Compositions

2. APPLICANT
NAME : Micro Labs Limited
NATIONALITY : Indian
ADDRESS : CTS No. 73, Saki Estate, Off Chandivali Road, Chandivali, Kurla (W),
Mumbai - 400 072, Maharashtra, India.
3, PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to lactose based coating for pharmaceutical compositions, which is resistant to discoloration of pharmaceutical compositions, wherein the lactose-based coating is free of any traditional excipients.
BACKGROUND OF THE INVENTION:
Coatings for the pharmaceutical compositions are an integral part of the compositions. These are applied generally for various purposes, including protection of the drug from the surrounding (environment, air, light and moisture) and thus improve stability, masking unpleasant taste or odor of the drug, improving product appearance and helping in brand identification, facilitating rapid identification by the manufacturer, the pharmacist and the patient, increasing the mechanical strength of the product, masking batch differences in the appearance of raw materials, prevention from destruction by gastric acid or gastric enzymes, making it easier for the patient to swallow the product and preparing the modified release drug delivery systems. The coatings are of different types and include functional coatings and non-functional coatings.
The commonly used materials for coatings include hypromellose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, carboxymethylcellulose sodium, hydroxy propyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, ethyl cellulose, hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, polymethacrylates, and shellac.
Various attempts have been made to prepare coatings based on newer materials, which are compatible with the substrate, easy to prepare with minimum level of excipients with better shelf life properties.

US 5,885,617 disclose polyvinyl alcohol based coatings. This product is commercially available as Opadry .
WO 87/007902 discloses coatings based on polydextrose for aqueous film coatings of pharmaceutical, food and confectionery products.
WO 07/063553 discloses aqueous film coating compositions based on sodium alginate along with plasticizer and other optional pharmaceutically acceptable inert excipients.
WO 09/024992 discloses dry film coating compositions comprising of tribasic calcium phosphate as one of the essential ingredient along with other commonly used polymers and plasticizers.
WO 10/052727 discloses dry film coating compositions comprising of a mixture of low viscosity hydroxy propyl methylcellulose and modified starch as essential components.
Lactose is a pharmaceutical excipient used widely in the pharmaceutical compositions. It is used as a diluent or as filler in the pharmaceutical compositions. Lactose has been traditionally used as a coating agent for the sugar coatings purposes. Furthermore US 5,630,871 discloses film coating compositions based on lactose and cellulosic film forming polymers.
WO 2005/009407 discloses coating of lactose on the Olanzapine particles or powder particles.
Thus there is still unmet need to develop a stable pharmaceutical composition having lactose coating resistant to discoloration of pharmaceutical compositions, wherein lactose coating is free of any traditional excipient.

SUMMARY OF THE INVENTION:
In one embodiment, the present invention provides a solid pharmaceutical composition comprising: a core comprising of an active ingredient; a coating comprising lactose; and optionally film coating over the lactose coat, wherein, lactose coating is free of traditional excipients.
In yet another embodiment, the present invention provides a process of making solid pharmaceutical composition comprises: dispersing or dissolving lactose in suitable solvents at a concentration range of 1 % w/v to 60 % w/v based on the weight of solvent; applying lactose dispersion or solution directly to the core containing olanzapine with loading in the range of 4-12% w/w; and optionally applying film coating over the lactose coat, wherein, lactose coating is free of traditional excipients.
In yet another embodiment, the present invention provides a process of making solid pharmaceutical composition comprises: dispersing or dissolving lactose in suitable solvents at a concentration range of 1 % w/v to 60 % w/v based on the weight of solvent; applying lactose dispersion or solution directly to the core containing olanzapine with loading in the range of 8% w/w; and optionally applying film coating over the lactose coat, wherein, lactose coating is free of traditional excipients.
In one another embodiment, the present invention provides a solid pharmaceutical composition comprising: a core comprising of an active ingredient; a coating comprising lactose; and a film coating over the lactose coat, wherein, lactose coating is free of traditional excipients, further the solid pharmaceutical composition is stable during the shelf life.
In yet another embodiment, the present invention provides a coating solution or dispersion comprising: lactose; and active ingredient, wherein coating solution or dispersion is directly applied as a layer on a core.

DETAILED DESCRIPTION OF THE INVENTION:
There are provided lactose based coatings for pharmaceutical compositions.
The inventors have developed lactose-based coatings for pharmaceutical compositions. Thus, there are provided lactose-based coatings, which can be applied directly for pharmaceutical compositions.
The commonly used solvents for preparing the coatings include purified water, alcohols like ethanol, methanol, butyl alcohol, ketones like acetone, methylethyl ketone, halogen containing compounds like methylene chloride, chloroform and the like.
The coatings are useful for direct application on to the pharmaceutical compositions. It has several advantages. Lactose being a commonly used pharmaceutically acceptable inert excipient in the pharmaceutical compositions, there are no compatibility issues with respect to the most of the active ingredients or other pharmaceutically acceptable inert excipients. Furthermore, this coating system does not involve traditional excipients like plasticizers or other film formers. This also eases the process for applying the coating to the pharmaceutical compositions. This coating has been shown to have shelf life stability.
In one embodiment, lactose may be in the form of crystalline or amorphous powder. Lactose is in hydrous form.
In one another embodiment, lactose as used herein includes lactose with a maximum particle size of up to 150 um. The d (90) value of the same may be in the range of 1 UJTI to 140 um.
In one another embodiment, the lactose may be in the form of spray-dried lactose.
The particle size of lactose is the critical parameter for lactose-based coatings. The larger particle size of lactose leads to rough surface of the coated pharmaceutical composition. The commercially available lactose grades like Pharmatose® may be used.

In one another embodiment, there is provided process for preparing lactose-based coatings. The lactose-based coatings are obtained by dispersing or dissolving lactose in suitable solvents at a concentration range of 1 % w/v to 60 % w/v based on the weight of solvent. Purified water is a solvent of choice. Other organic solvents like ethyl alcohol # and isopropyl alcohol may also be used.
At lower concentrations up to 12 %, lactose readily gets dissolved in purified water to form a solution. At concentrations above this, lactose gets dispersed into purified water to form dispersion. Thus, the lactose-based coatings may be in the form of solution or dispersion.
In one another embodiment, the pharmaceutical composition contains one or more active ingredients. The pharmaceutical composition may be a solid dosage form. The solid dosage form may be one or more of tablet, capsule, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and the like. The solid dosage form also includes multilayer tablets. The pharmaceutical composition further comprises one or more pharmaceutically acceptable inert excipients. The pharmaceutically acceptable inert excipients may be one or more of diluents, disintegrants, lubricants, glidants and the like,
The pharmaceutical composition comprises active pharmaceutical ingredient. The active ingredient may be one or more of therapeutic categories selected from adrenergic blocking agents, antacids, anti-asthmatic agents, anti-allergic agents, anti-cholesterolemic and anti-lipid agents, anti-cholinergics and sympathomimetics, anti-coagulants, anticonvulsants, anti-diarrheal, anti-emetics, anti-hypertensive agents, anti-infective agents, anti-inflammatory agents non-steroidal anti-inflammatory agents, anti-malarials, anti-manic agents, anti-nauseants, anti-neoplastic agents, anti-obesity agents, antiparkinsonian agents, anti-pyretic, anti-spasmodic agents, anti-thrombotic agents, anti-uricemic agents, anti-anginal agents, antihistamines, anti-tussives, appetite suppressants, benzophenanthridine alkaloids, cardio active agents, cerebral dilators, coronary dilators,

decongestants, diuretics, diagnostic agents, hypnotics, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypoglycemic agents, laxatives, mineral supplements, mitotics, mucolytic agents, neuromuscular drugs, peripheral vasodilators, progestational agents, psychotropics, sedatives, stimulants, thyroid and anti-thyroid agents, tranquilizers, uterine relaxants, vitamins, antigenic materials and the like.
The non limiting examples of the drugs include paracetamol, pseudoephedrine, acravastine, iamivudine, abacavir, pravastatin, Roziglitazone, ezetimibe, Clavulanate, sulfamethoxazole, benazepril, Valsartan, Irbesartan, Losartan, Dutasteride, tamsolusin, Atazanavir, ritonavir, propoxyphene, Hydrocodone, Metocarbamol, Memantine, Donepezil, Glyburide, Pioglytazone, Glimepiride, Benazepril, Torcetrapib, Eprosartan, Telmisartan, Olmesartan, Lopinavir, Emtricitabine, Tenofovir, Amprenavir, Tipranavir, Atovaquone, Proguanil, 5-aminosalicylic acid, 4-aminophthalic acid, Bismuth citrate, Bismuth subsalicylate, Montelukast, pseudoephedrine, Guaifenesin, ibuprofen, nifedipine, betamethasone acetate, methylprednisolone, dextromethorphan, cinnarazine, simvastatin, ciprofloxacin, glipizide, risperidone, glibenclamide, fenofibrate, isosorbide mononitrate, isosorbide dinitrate, acetazolamide, levothyroxine sodium, omeprazole, aspirin, codeine, dihydroergotamine, diazepam, theophylline, sildenafil citrate, vardenafil hydrochloride, amlodipine besylate, Zolpidem tartrate, acetaminophen, methocarbamol, ramipril, digoxin, enalapril maleate, fluoxetine hydrochloride, fexofenadine hydrochloride, olanzapine, methyldopa, hydrochlorothiazide, timolol maleate, alendronate sodium, thiabendazole, rofexocib, dicoflenac, bepridil hydrochloride, atorvastatin hydrochloride, sertraline hydrochloride, famciclovir monohydrate, nabumetone, cimetidine, ketoprofen, etodolac, amiodarone hydrochloride, indomethacin, cefaclor, diltiazem, verapamil, felodipine, isradipine, nicardipine, prazosin, disopyramide, pentoxifylline, venlafaxine, alfuzosin, doxazosin, famotidine, ranitidine, pirenzipine, lansoprazole, loperamide, sulfasalazine, prednisolone, furosemide, amiloride, triamterene, verapamil, atenolol, propranolol, captopril, glyceryl trinitrate, caffeine, aminophylline, cetirizine, loratadine, chlorpheniramine maleate, diphenhydramine, dothiepin, amitriptyline, phenelzine, paroxetine, fenfluramine, dimenhydrinate, ondansetron, domperidone, metoclopramide, tramadol, dihydrocodeine, pethidine,

sumatriptan, amoxicillin, ampicillin, cefuroxime, cephalexin, tetracycline, erythromycin, co-trimoxazole, sulphadiazine, trimethoprim, nitrofurantoin, fluconazole, ketoconazole, acyclovir, zidovudine, chloroquine, mefloquin, metronidazole, metformin, chlorpropamide, ferrous sulphate, azapropazone, fenbufen, flurbiprofen, ketoprofen, naproxen, piroxicam, mefanamic acid, celecoxib, licofelone, tadalafil, mycophenolate, valgancyclovir, valacyclovir, sevelamer, metaxolone, nelfinavir, duranavir, tipranavir, levetiracetam, capecitabine, moxifloxacin, morphine, levofloxacin, clarithromycin, pregabalin, esomeprazole, quetiapine, efavirenz, oxcarbazepine, colesevelam, zileuton, nitazoxanide, clofibrate, praziquantel, sucralfate, cefprozil, indinavir, ganciclovir, oxaprozin, divalproex, cefadroxil, felbamate, potassium chloride, saquinavir, fosamprenavir, hydroxyurea, gabapentin, niacin, omega-3 acid ethyl esters, calcium acetate, progesterone, procainamide, delavirdine, ribavirin, propafenone, eprosartan, tocamide, tinidazole, choline magnesium trisalicylate, azithromycin, linezoiid, lorazepam, oxazepam, lormetazepam, flunitrazepam, haloperidol, triptorelin, leuprorelin, lanreotide acetate, octreotide acetate, methylxanthin, tamsulosin, codeine hydrochloride, dextromoramide tartrate, ethymorphine hydrochloride, magnesium salicylate, methadone hydrochloride, oxycodone hydrochloride, sufentanil citrate, ephedrine, tramazoline hydrochloride, brompheniramine maleate, emedastine fumarate, and pharmaceutically acceptable salts, acids, esters, isomers, and metabolites thereof.
The lactose coatings may be applied to the pharmaceutical compositions by using any conventional coating techniques like pan coating, spray coating, dip coating, dusting, compression coating and the like. The commonly used equipments like fluidized bed processor may also be used. The processing parameters and the application of coating to the pharmaceutical composition may be known to the person skilled in the art.
In one another embodiment, the pharmaceutical compositions, which are coated with lactose-based coatings, may further be coated with film coatings. Thus, the lactose-based coating may function as a barrier or seal coat.

The film coatings may comprise one or more of film formers, solvents, plasticizers and the like.
Suitable film formers may be one or more of hydroxypropyl methyl cellulose, methyl hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, polyethylene glycol, acrylates and the like.
Suitable solvents may be one or more of water, ethanol, methanol, isopropanol, chloroform, acetone, methylethyl ketone, methylene chloride and the like.
Suitable plasticizers may be one or more of propylene glycol, castor oil, glycerin, polyethylene glycol, polysorbates, and the like.
In one another embodiment, a layer of drug is applied directly to the pharmaceutical compositions, which are coated with lactose-based coatings. Thus, the pharmaceutical composition may be a multilayered pharmaceutical composition.
In one another embodiment, the lactose-based coatings may comprise active pharmaceutical ingredient. The lactose-based coatings inclusive of active pharmaceutical ingredient may be coated as a layer on pharmaceutical composition. The lactose-based coatings inclusive of active pharmaceutical ingredient may also be coated over beads or non-pareil seeds or inert carriers.
The lactose-based coatings on the composition possess shining smoothness, less tackiness. Further, the adhesion of lactose based coating to the pharmaceutical composition is good.
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

Example-1

SR. NO. INGREDIENTS % WEIGHT
1. Olanzapine 4.902
2. Lactose Anhydrous 82.843
3. Crospovidone 1.471
4. Microcrystalline Cellulose 9.804
5. Magnesium Stearate 0.980
Lactose coating
6. Lactose Monohydrate 8.00
7. Purified water q.s.
Film coating
8. Hypromellose 5cps 1.985
9. Macrogol 6000 0.184
10. Titanium Dioxide 0.735
11. Polysorbate 80 0.037
12, Isopropyl alcohol q.s.
13. Methylene chloride q.S.

Manufacturing Process in brief:
1.0 SIFTING:
1.1 Sift Microcrystalline Cellulose, Crospovidone, Anhydrous Lactose separately using # 40 Stainless Steel sieve.
1.2 Sift Olanzapine together with sifted Crospovidone, Microcrystalline Cellulose using # 40 Stainless Steel sieve.
2.0 DRY MIXING: Charge the sifted materials into the Bin in the following order: Half quantity of the sifted Anhydrous Lactose, Olanzapine Premix, Microcrystalline cellulose, Crospovidone (Step 10.7) and add remaining quantity of Anhydrous Lactose and mix for 30 min at slow speed.
3.0 LUBRICATION: Sift Magnesium Stearate using # 60 mesh S.S. Sieve and mix with dry mix blend for 3 minutes at SLOW speed
4.0 Compression: Compress lubricated blend using the suitable punch set.
5.0 Seal Coating:
5.1.1 Disperse Lactose Monohydrate in weighed quantity of Purified water under stirring. Stir continuously for 45 min in order to get uniform dispersion.
6.0 FILM COATING:
6.1 Film Coating solution preparation

6.1.1 Divide the mixture of Isopropyl alcohol and Methylene chloride approx. three equal parts.
6.1.2 Dissolve Hypromellose 5cps, Polysorbate 80 & Macrogol 6000 in part I of the solvent mixture.
6.1.3 Disperse Titanium Dioxide in part-II of solvent mixture under stirring and pass

through Flameproof colloid mill for 15 minutes.
4 Rinse the colloid mill with remaining part-Ill of solvent mixture & transfer the suspension in step 6.1.3 and Mix for 2 minutes.
5 Add the suspension of step no. 6.1.3 to step no. 6.1.2 and mix for 5 minutes.
6 Strain the above suspension through nylon cloth.

Stability data:
Table 1: Stability data of formulation of example 1 under accelerated conditions

Tests Specification Initial 40°C±75% RH

1 Month 2 Months 3 Months
Appearance White colored, White colored, White colored, oval White colored, oval White colored, oval
oval shaped, oval shaped, shaped, biconvex, film shaped, biconvex, film shaped, biconvex, film
biconvex, film biconvex, film coated tablets, plain on coated tablets, plain on coated tablets, plain on
coated tablets, plain on both faces. coated tablets, plain on both faces both faces both faces both faces
Average Mass For information only 456.00 mg 456.26 mg 456.67 mg 456.84 mg
Dissolution (by UV) Not less than 75% 98.2 % 102.1% 97.6 % 96.7 %
(Q) of labeled amount is dissolved in 30 minutes. (95.9% to 100.6
%) (98.4% to 104.4%) (96.6 % to 99.4 %) (95.0 % to 98.2 %)
Assay (By HPLC) Between 95.0% 100.3% 101.0% 98.8 % 99.4 %
each film tablet and 105.0% of
contain Olanzapine label claim

Table 02: Stability data with respect to related substances of formulation of example 1 under accelerated conditions

Tests Specification Initial 40°C±75% RH

1 Month 2 Months 3 Months
Water content For information only 1.27% 1.05% 1.20% 1.08%
Related Substances
(By HPLC)
a) Impurity crystallised amine
b) Impurity piperazitiium chloride
c) Impurity Dimethyl
d) Impurity Lactam
e) Impurity N- Oxide
i) Single unknown impurity g) Total impurity Not more than 0.50 % Not more than 0.50 % Not more than 0.50 % Not more than 0.50 % Not more than 0.20 % hlot more than 0.20 % Not more than 2.0 % 0.01 0.07 0.01 0.02 0.02 0.02 0.23 0.02 0.05 0.01 0.08 0.06 0.04 0.35 0.02 0.04 0.01 0.13 0.05 0.03 0.33 0.02 0.04 0.02 0.21 0.07 0.03 0.45

We claim:
1. A solid pharmaceutical composition comprising:
a core comprising of an active ingredient;
a coating comprising lactose; and
optionally film coating over the lactose coat,
wherein, lactose coating is free of traditional excipients.
2. The solid pharmaceutical composition claimed in claim 1, wherein an active ingredient is olanzapine.
3. The solid pharmaceutical composition claimed in claim 1, wherein lactose used is spray-dried lactose.
4. The solid pharmaceutical composition claimed in claim 1, wherein lactose has particle size below 150 μm and d (90) value in the range of 1 μm to 140 μm
5. The solid pharmaceutical composition claimed in claim 1, is stable under the accelerated conditions for 3 months.
6. A process of making solid pharmaceutical composition comprises:
dispersing or dissolving lactose in suitable solvents at a concentration range of 1 %
w/v to 60 % w/v based on the weight of solvent;
applying lactose dispersion or solution directly to the core containing olanzapine with
loading in the range of 4-12% w/w; and
optionally applying film coating over the lactose coat,
wherein, lactose coating is free of traditional excipients.
7. The solid pharmaceutical composition claimed in claim 6, wherein lactose used is spray-dried lactose.
8. The solid pharmaceutical composition claimed in claim 6, wherein lactose has particle size below 150 μm and d (90) value in the range of 1 urn to 140 μm.
9. The solid pharmaceutical composition claimed in claim 6, is stable under the accelerated conditions for 3 months.