FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION: "Stable Formulations for Inhalation
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.

Technical field:
The present invention relates to stable and novel aerosol formulations suitable for pulmonary, nasal, buccal or topical administration. It also relates to process for manufacturing the same.
Background and prior art
Drugs for treating respiratory disorders are frequently administered in oral aerosol formulations. One widely used method for dispensing such an aerosol drug formulation involves making a formulation of the drug in a liquefied gas known as a propellant. The drug may be dissolved or suspended in the propellant, or in a combination slurry-solution.
Chlorofluorocarbons (CFCs) have been used extensively as propellants in drug formulations that are delivered to patients via an MDI. However, recent scientific evidence suggests that CFCs damage the Earth's ozone layer. It is believed that ozone blocks harmful ultraviolet rays and that depletion of the ozone layer will result in the incidence of skin cancer. As a result, steps have been taken to reduce CFC production and usage, and recent recommendations have been made that CFC production be virtually discontinued and alternate ozone free propellants should be used.
MDI formulations containing HFA propellants do not have suspension characteristics as good as those formulations containing CFC Propellants. For example, an MDI formulation containing the beta-agonist albuterol sulfate and an anticholinergic agent, such as ipratropium bromide or tiotropium, with an HFA propellant is not a stable suspension and either quickly sediments or forms an emulsion.
As a result surfactants have been used in aerosol formulations containing HFA to improve the quality of the Aerosol suspensions.
U.S. Pat. No. 5,182,097 to Byron et al. relates to aerosol formulations consisting of 1,1,1,2-tetrafluoroethane, a drug and oleic acid as a surfactant to aid in dispersing the drug in the propellant.
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U.S. Pat. No. 5,612,053 to Baichwal et al. relates to respirable dry powder formulations comprising controlled release particles of a cohesive composite of a drug and a carrier, wherein the carrier is a natural polysaccharide gum added as filler.
Attempts have also been made to coat drug with only surfactants or instead, but the results have not been very satisfactory. Therefore there still remains a need to provide novel ways to solve the problem of sedimentation and stability of suspension.
Objectives of the invention:
The object of the present invention is to provide a stable pharmaceutical aerosol formulation.
Another object of the present invention is to provide a pharmaceutical aerosol formulation that overcomes the problem of sedimentation and stability of suspension.
Still another object of the present invention is to provide a process to manufacture the pharmaceutical formulation according to the present invention.
Summary of the invention:
Thus according to a first aspect of the present invention there is provided a pharmaceutical aerosol formulation comprising the drug coated with polyvinylpyrrolidone ("PVP")in combination with a propellant.
According to a second aspect of the present invention there is provided a pharmaceutical aerosol formulation comprising the drug coated with PVP and surfactant in combination with a propellant.
In a third aspect of the present invention the pharmaceutical aerosol formulation according to the first and second aspect further comprises either other suitable excipients or similarly coated or uncoated drug particles.
In a fourth aspect of the present invention there is provided a process to manufacture a pharmaceutical aerosol formulation according to the present invention.
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Detailed description of the invention:
As discussed earlier there is a need to provide novel ways to solve the problem of sedimentation and stability of suspension.
The present invention provides a stable pharmaceutical aerosol formulation. More specifically, the stable pharmaceutical aerosol formulation contains a pharmaceutically active agent coated with PVP in combination with a hydrofluoroalkane ("HFA") propellant and optionally other suitable excipients.
The present invention also provides a stable pharmaceutical aerosol formulation comprising a pharmaceutically active agent coated with PVP and surfactant in combination with a hydrofluoroalkane ("HFA") propellant and optionally other suitable excipients.
As discussed earlier, aerosol formulations traditionally contained CFC propellants. Due to environmental concerns, HFA propellants are now preferred over CFC propellants. As will be understood by those skilled in the art, suitable HFA propellants for use in the present invention include, but are not limited to, 1,1,1,2-tetrafluoroethane (HFA-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA-227). Optionally mixtures of two or more such halogen-substituted hydrocarbons may also be used.
We have surprisingly found that when the drug is coated with PVP, the PVP maintains the homogeneity of the suspension. .Suitably PVP (polyvinylpyrrolidone), such as PVP K17, PVP K25 or PVP K30. The PVP can be present in a range of about 0.00001% to about 10% by weight of the formulation. Suitably, the PVP is present in a range of about 0.00001% to about 0.1% or about 0.0001% to about 0.001% by weight of the formulation.
The invention is particularly useful in that it allows acceptably stable dispersions to be attained using HFA Propellant as the aerosol propellant. The formulations of the invention may be prepared with HFA Propellant alone or a mixture of HFA Propellant and another miscible adjuvant having a polarity equal to or lower than the polarity of the HFA Propellant.
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Suitable solid medicaments may include for eg. antiallergics, analgesics, bronchodilators, antihistamines, thereapeutic proteins and peptides, antitussives, anginal preparations, antibiotics, antiinflammatory preparations, hormones, or sulfonamides, such as, for example, a vasoconstrictive amine, an enzyme, alkaloid, or steroid, and synergistic combinations of these. Examples of medicaments which may be employed are: Isoproterenol [alpha-(isopropylaminomethyl) protocatechuyl alcohol], phenylephrine, phenylpropanolamine, glucagon, adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin, morphine, dihydromorphinone, ergotamine, scopolamine, adrenaline, metaproterenol, phenylephrine, phenylpropanolamine, reproterol, isoetharine, tulobuterol, orciprenaline, or(-)-4-amino-3,5 -dichloro- a-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol; diuretics, e.g.amiloride methapyrilene, cyanocobalamin, terbutaline, rimiterol, salbutamol, salmeterol, formoterol, carmoterol, fenoterol, ipratropium, oxitropium, tiotropium, triamcinolone, budesonide, fluticasone, tipredane, mometasone, ciclesonide, flunisolide, colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl, and diamorphine, diltiazem. Others are antibiotics, such as neomycin, streptomycin, penicillin, procaine penicillin, sulphonamides, pentamidine, tetracycline, chlorotetracycline and hydroxytetracycline; adrenocorticotropic hormone and adrenocortical hormones, such as cortisone, hydrocortisone, hydrocortisone acetate and prednisolone; insulin, antiallergy compounds such as cromolyn sodium, ketotifen ornedocromil etc. xanthines e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g. insulin or glucagons.
The therapeutic agents mentioned above as well as the drugs throughout the specification are used in a broad sense to include not only various therapeutic agents and drugs per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
The following salts of the drugs mentioned above may be used; acetate, benzenesulphonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate,
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esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulphate, tannate, tartrate, and triethiodide.
Cationic salts may also be used. Suitable cationic salts include the alkali metals, e.g.
sodium and potassium, and ammonium salts and salts of amines known in the art to be
pharmaceutically acceptable, e.g. glycine, ethylene diamine, choline, diethanolamine,
triethanolamine, octadecylamine, diethylamine, triethylamine, l-amino-2-propanol-
amino-2-(hydroxymethyl)propane-1,3-diol and 1 -(3,4-dihydroxyphenyl)-2
isopropylaminoethanol.
Preferred drugs for the invention are betamimetics and anticholinergics. The terms "betamimetics" or "anticholinergic agent" are used in a broad sense to include not only the betamimetics or anticholinergic agent per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof
Betamimetic agents useful in the formulations of the present invention include, but are not limited to, albuterol, formoterol, levalbuterol, carmoterol, pirbuterol and salmeterol. The international name for albuterol is salbutamol. Suitable pharmaceutically acceptable salts of the betamimetics include, but are not limited to the hydrochloride, sulfate, maleate, tartrate, and citrate salts. Suitably, the betamimetic is albuterol or albuterol sulfate.
Anticholinergic agents useful in the formulations of the present invention include, but are not limited to,oxitropium, ipratropium and tiotropium. Suitable pharmaceutically acceptable salts of the anticholinergic agents include, but are not limited to, the halide
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salts such as bromide, chloride and iodide. Suitably, the anticholinergic agent is ipratropium or ipratropium bromide or ipratropium bromide monohydrate.
In addition to the PVP, the drug may be coated with a surfactant. Suitable surfactants include sorbitan trioleate, tweens for eg. tween 20,40,60,80,120, Lipids, lecithin,oleic acid, citric acid, and polyoxyethylene(4)lauryl ether (Brij 30®). Suitably the surfactant is tween 80. The surfactant can be present in a range of about 0.00001-0.01% by weight of the active.
The solvent used for dissolving the PVP or the surfactant should be such that the selected drug is either insoluble or has a suitably low solubility in the selected solvent.
In another aspect, the present invention describes a method for Coating Drug Particles with PVP. This method remains a general method for coating the drug particles.
A solution of PVP is prepared in a solvent in which the selected drug is either insoluble or has a suitably low solubility. The concentration, of the PVP solution varies with the selected drug but is typically less than 10% by weight of the formulation and more usually in the range 0.00001 to 0.1% by weight of the formulation. The micronized drug powder is added to the above solution of PVP and mixed with techniques known in the art for eg.sonicating for about 30 min to give a homogeneous suspension. Micronized drug powder is defined as comprising particles having a mean size in the range of 1 to 5 urn. After mixing, the drug particles are coated with a layer of above PVP solution. Coated particles are separated from the suspension by techniques known in the art, for eg. spraying through a suitable spray drier and dried. The powder is collected and deaggregated to produce a free flowing powder. Optionally the powder may be subjected to conventional milling techniques to give appropriate size to the drug particles. The appropriate quantity of the coated drug and propellant are then admixed in a suitable container to give final suspension.
In another aspect, the present invention describes a method for Coating Drug Particles with PVP and surfactant. This method remains a general method for coating the drug particles.
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A solution of PVP and surfactant is prepared separately in a solvent in which the selected drug is either insoluble or has a suitably low solubility. The concentration, of the PVP and surfactant solution varies with the selected drug. An appropriate quantity of the surfactant solution is mixed with the solution of PVP and to this resultant solution is added the micronized drug powder and mixed with techniques known in the art for eg.sonicating for about 30 min to give a homogeneous suspension. Micronized drug powder is defined as comprising particles having a mean size in the range of 1 to 5 urn After mixing, the drug particles are coated with a layer of above PVP and surfactant solution. Coated particles are separated from the suspension by techniques known in the art, for eg. spraying through a suitable spray drier and dried. The powder is collected and deaggregated to produce a free flowing powder. Optionally the powder may be subjected to conventional milling techniques to give appropriate size to the drug particles. The appropriate quantity of the coated drug and propellant are then admixed in a suitable container to give final suspension.
The coated drug particles with either of the two methods may further be mixed with other similarly coated or uncoated drugs and/or one or more suitable excipients selected from the group consisting of cosolvents, bulking agents, antioxidants, lubricants. In another aspect the coated drug may be mixed with other similarly coated or uncoated drugs and optionally with surfactants.
The formulation may include cosolvent, such as polyethylene glycol ("PEG"), propylene glycol, isopropyl myristrate or glycerol. Suitably, the cosolvent is PEG, such as PEG 200 or PEG 400. The cosolvent can be present in a range of about 0.05% to about 15% by weight of the formulation. Suitably, the cosolvent is present in a range of about 0.05% to about 1% or about 0.05% to about 0.3% by weight of the formulation.
The formulation may comprise bulking agent may be selected from the class of saccharides, including but not limited to monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol.. The bulking agent may be present in a concentration of 10-500%. More preferably in a range of 10-300%. The preferred bulking agent is Lactose.
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The present invention may optionally contain antioxidants like citric acid, benzalkonium chloride.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Manufacture of coated drug:
Example 1
0.5% w/w( of medicament) of PVP K17 is dissolved in about 250 ml of dried acetone and sonicated. To this solution salbutamol sulphate is added and sonicated for about 30 min. This is then further spray dried to obtain coated salbutamol.
Example 2
50 mg of Tween 80 is added in 100ml of alcohol and sonicated.0.5% w/w (of medicament) of PVP K17 is dissolved in about 250 ml of dried acetone and sonicated. To this solution is added about 0.02 ml of above prepared tween 80 solution. To this solution salbutamol sulphate is added and sonicated for about 30 min. this is then further spray dried to obtain coated salbutamol.
Formulation 1

Qty/can
Ipratropium Bromide monohydrate 5.04 mg
Albuterol Sulfate coated with 0.5%PVP K17 28.8 mg
HFA-227 Q.s
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a) The active ingredients were added to the canister.
b) the canister was crimped with the metered valve
c) the canister was charged with HFA227 .
Formulation 2

Qty/can
Ipratropium Bromide monohydrate 5.04 mg
Albuterol Sulfate coated with 0.5%PVP K17 28.8 mg
lactose 4.23 mg
HFA-227 Q.s
(a) The active ingredients to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with the propellant.
Formulation 3

Qty/can
Ipratropium Bromide monohydrate 5.04 mg
Albuterol Sulfate coated with 0.5%PVP K17 28.8 mg
lactose 4.23 mg
PEG 400 16.8 mg
HFA-227 Q.s
(a) The active ingredients to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with the solution of propellant and PEG.
Formulation 4

Qty/can
Ipratropium Bromide monohydrate 5.04 mg
Albuterol Sulfate coated with 0.5%PVP K17 28.8 mg
lactose 4.23 mg
PEG 400 50.4 mg
HFA-227 Q.s
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(a) The active ingredients to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with the solution of propellant and PEG.
Formulation 5

Qty/can
Ipratropium Bromide monohydrate 5.04 mg
Albuterol Sulfate coated with 0.5%PVP K17and0.0002%tween80 28.8 mg
lactose 4.23 mg
HFA-227 Q.s
(a) The active ingredients to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with the propellant.
Formulation 6

Qty/can
Ipratropium Bromide monohydrate 5.04 mg
Albuterol Sulfate coated with 0.5%PVP K17 and 0.0002% tween 80 28.8 mg
lactose 4.23 mg
PEG 400 16.8 mg
HFA-227 20.2 gm
(a) The active ingredients to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with the solution of propellant and PEG.
Formulation 7

Qty/can
Ipratropium Bromide monohydrate 5.04 mg
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Albuterol Sulfate coated with 0.5%PVP K17 and 0.0002% tween 80 28.8 mg
lactose 4.23 mg
PEG 400 16.8 mg
HFA-227 20.2 gm
(a) The active ingredients to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with the solution of propellant and PEG.
Table 1. Effect of combinations of drug coated with Surface modifying or PVP and surfactant on the suspension characteristics and Suspension quality of ipratropium bromide and albuterol sulfate.

Active Ingredients Cosolvent Bulking agent Propellant Suspensioncharacteristicsandsuspensionquality.
1 Ipratropium (5.04 mg) Albuterol sulfate (28.8 mg) HFAPropellant (PI34a or P227) Particles remain in homogeneous suspension for less than 5 seconds.
2 Ipratropium (5.04 mg) Albuterol sulfate coated with only surfactant (28.8 mg) HFAPropellant (PI 34a or P227) Particles remain in homogeneous suspension for about 20-25 seconds.
3 Ipratropium (5.04 mg) Albuterol Sulfate coated with 0.5%PVP K17 (28.8 mg) HFAPropellant (PI 34a orP227) Particles remain in homogeneous suspension for about 35 seconds to 1 minute.
4 Ipratropium (5.04 mg) Albuterol Sulfate coated with 0.5%PVP K17 (28.8 mg) PEG 200/400 (0.1% and 0.3% of total formulation) HFAPropellant (PI34a or P227) Particles remain in homogeneous suspension for about 35 seconds to 1
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minute.
5 Ipratropium (5.04 mg) Albuterol Sulfate coated with 0.5%PVP K17 (28.8 mg) PEG200/ 400 (0.1% and 0.3% of total formulation) 12.5% of total active HFAPropellant (PI34a or P227) Particles remain in homogeneous suspension for about 35 seconds to 1 minute.
6 Ipratropium (5.04 mg) Albuterol Sulfate coated with 0.5%PVP K17 and 0.0002% tween 80 (28.8 mg) 12.5% of total active HFAPropellant (PI34a or P227) Particles remain in homogeneous suspension for about 35 seconds to 1 minute.
7 Ipratropium (5.04 mg) Albuterol Sulfate coated with 0.5%PVP K17 and 0.0002% tween 80 (28.8 mg) PEG200/ 400 (0.1% and 0.3% of total formulation) 12.5% of total active HFAPropellant (PI 34a or P227) Particles remain in homogeneous suspension for about 35 seconds to 1 minute.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a propellant" includes a single propellant as well as two or more different propellants, reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.

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