FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION: "Stable Aerosol Formulation"
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 Aerosol formulations used for the administration of medicaments by inhalation.
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.
MDIs contain drugs which are dissolved or suspended as micronized particles, propellants in the form of liquefied gases, and surface active compounds, or "surfactants," of a type and in a concentration suitable for suspension or dissolution of the drug. Surfactants are included in the formulation to improve particle dispersibility, prevent deaggregation and improve valve function by virtue of its lubricating properties. In some solution formulations, a co-solvent may be added to enhance drug dissolution, although this practice may have the disadvantage of decreasing the fraction of the metered dose which may be inhaled and contributing to particle size growth.
HFC 134a, or 1, 1, 1, 2-tetrafluoroethane (the names will be used interchangeably herein) is nonflammable, has low toxicity and has vapor pressure suitable for use in aerosols. However, HFC 134a is a very poor solvent which fails to dissolve or adequately disperse
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commonly used surfactants such as sorbitan trioleate, sorbitan monooleate, lecithins and oleic acid in useful concentrations without the aid of a co-solvent.
Similarly, HFC 227, or 1, 1,1,2,3,3,3-heptafluropropane (the names will be used interchangeably herein) is nonflammable, has low toxicity and has a vapor pressure suitable for use in aerosols. However, the polarity and solubility of HFC 227 differ from those of commonly used CFC propellants, and many commonly used surfactants are not soluble or are poorly dispersible in HFC 227.
Thus, there remains a need for a method for aiding in the incorporation, dispersion and solubilization of drugs and excipients in aerosol formulations utilizing hydrofluorocarbon propellants such as HFC 134a and HFC 227.
US 5182097 belongs to Byron et al., discloses 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.
US 5612053 belongs to Baichwal et al., describes 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 a filler.
Surprisingly, the applicants have now found that bulking agents, surface modifying agents may advantageously be used to prepare novel aerosol formulations. In addition when such an aerosol formulation is manufactured by co spray drying process it results in an aerosol formulation that is a stable and uniform suspension.
Object of the invention
The object of the present invention is to provide a stable and uniform aerosol formulation.
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It is another object of the present invention to provide a process for the manufacture of the stable and uniform aerosol formulations.
It is yet another object of the present invention to provide a method of treatment which comprises administration of medicament for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment.
Summary of the invention
According to the present invention there is provided a stable aerosol formulation comprising:
a) atleast one particulate drug;
b) atleast one bulking agent;
c) atleast one surface modifying agent; and c) atleast one hydrofluorocarbon propellant.
According to the present invention there is also provided a stable aerosol formulation comprising atleast one particulate drug; atleast one bulking agent; atleast one surface modifying agent, which are co spray dried and dispersed in one or more hydrofluorocarbon propellant.
There is also provided a process for manufacturing the stable aerosol composition according to the present invention.
Description of the invention
As described above, in order to overcome the difficulties faced in the prior art the present invention provides an aerosol formulation comprising a therapeutically effective amount of at least one particulate drug (active), atleast one bulking agent and atleast one surface modifying agent dispersed in a pharmaceutically acceptable propellant or mixture of such propellants. In a preferred embodiment, the propellant comprises at least one hydrofluorocarbon propellant.
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We have observed that addition of only Bulking agent into the formulation gave a formulation that was not stable over the stability. In particular it was observed that the particle size was not the same over stability. But we have surprisingly found that when an additional surface modifying agent such as PVP K 25/30 was co spray dried along with the bulking agent and the active ingredient(s) , desired particle size of the active ingredient(s) is achieved and hence keeping the formulation more stable over the stability. It was also found that the formulation exhibited uniform delivered dose characteristics throughout the life of the can.
The particle size of the particulate (e.g. micronised) drugs should be such as to permit substantially all of the particles to be potentially available for inhalation into the lungs upon administration of the powder composition. Thus, for example, at least 90%, preferably at least 95% by weight of the particles will have a diameter of less than 15 micrometers, preferably in the range of 1 to 10 micrometers, for example 1 to 5 micrometers.
The final aerosol formulation desirably contains 0.005-10% w/w, preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicament relative to the total weight of the formulation.
Drugs which may be administered in aerosol formulations according to the invention include any drug useful in inhalation therapy and which may be presented in a form which is substantially completely insoluble in the selected propellant. Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. dilfiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; antiinfectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine, adrenaline, fenoterol, formoterol,
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isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol,
reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol,
orciprenaline, or (-)4-amino-3,5-dichloro-.alpha.-[[[6-[2-(2-
pyridinyl)ethoxy]hexyl]amino]me thyl]benzenemethanol; diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g. insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs thereof to optimize the activity and/or stability of the medicament and/or to minimise the solubility of the medicament in the propellant.
The terms "broncodialators" or "anticholinergic agent" and the like are used in broad sense to include not only the beta-agonist or anticholinergic agent per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, etc.
Particularly preferred medicaments for administration using aerosol formulations in accordance with the invention include anti-allergies, anticholinergics, bronchodilators and antiinflammatory steroids of use in the treatment of respiratory disorders such as asthma by inhalation therapy, for example salbutamol, beclomethasone, ipratropium, Formoterol, tiotropium, salmeterol, Fluticasone, budesonide, fenoterol, ciclesonide, mometasone, tiotropium and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable derivatives, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs thereof are especially preferred.
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It will be appreciated by those skilled in the art that the aerosol formulations according to the present invention may, if desired, contain a combination of two or more active ingredients. Aerosol compositions containing two active ingredients (in a conventional propellant system) are known, for example, for the treatment of respiratory disorders such as asthma. Accordingly the present invention further provides aerosol formulations in accordance with the invention which contain two or more particulate medicaments.
Preferred aerosol formulations in accordance with the invention may comprise (a) an effective amount of a particulate bronchodilatory medicament, (b) an effective amount of a particulate antiinflammatory, preferably a steroidal antiinflammatory medicament, (c) atleast one hydrofluorocarbon propellant, (d) at least one bulking agent, (e) atleast one surface modifying agent. Particularly preferred aerosol formulations contain bronchodilators such as salbutamol (e.g. as the free base or as the sulphate salt), salmeterol (e.g. as the xinafoate salt) or isoprenaline in combination with an antiinflammatory steroid such as a beclomethasone ester (e.g. the diproprionate) or a fluticasone ester (e.g. the propionate). Alternatively aerosol formulations may contain a bronchodilator in combination with an antiallergic such as cromoglycate (e.g. the sodium salt). Combinations of isoprenaline and sodium cromoglycate, salmeterol and fluticasone propionate, or salbutamol and beclomethasone dipropionate are especially preferred.
In another alternative embodiment the stable aerosol formulations in accordance with the invention may comprise (a) an effective amount of a particulate bronchodilatory medicament, (b) an effective amount of a particulate anticholinergic medicament, (c) a hydrofluorocarbon propellant, (d) at least one bulking agent, (e) atleast one surface modifying agent. Particularly preferred aerosol formulations contain bronchodilators such as salbutamol (e.g. as the free base or as the sulphate salt), salmeterol (e.g. as the xinafoate salt) or isoprenaline in combination with an anticholinergic agents like ipratropium, tiotropium, oxitropium and the like.
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The typical bulking agents used in the formulation may include but are not limited to the class of saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol, sorbitol, maltitol, xylitol. Preferably the bulking agents may be present in a range 0.001 to 600% of the drug.
The surface modifying agents may include but are not limited to PVP K 25, PVP K 30.Preferably the surface modifying agent may be present in a range of 0.001 to 50% of the drug.
The formulations according to the present invention may optionally contain one or more excipients or carriers conventionally used in the art of pharmaceutical aerosol formulation. Such optional excipients include, but are not limited to, taste masking agents, buffers, antioxidants, water and chemical stabilizers.
As discussed earlier, aerosol formulations traditionally contained CFC propellants. Due to environmental concerns, HFC propellants are now preferred over CFC propellants. As will be understood by those skilled in the art, suitable HFC propellants for use in the present invention include, but are not limited to, 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227).
A particularly preferred embodiment of the invention provides a stable aerosol formulation comprising one or more particulate drug, one or more bulking agent, one or more surface modifying agent and one or more hydrofluorocarbon propellant.
The present invention further provides a method of manufacture of the present invention. The aerosol formulation may be prepared by preparing a solution of PVP in warm water and adding the bulking agent and the particulate drug into the solution and co-spray drying this solution to get fine coated drug particles.
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The coated drug so obtained may then be weighed in a suitable metal canister, crimped with a suitable valve and charged with HFA Propellant.
We further observed that some aerosol drugs tend to adhere to the inner surfaces, i.e., walls of the cans and valves, of the Aerosol Inhaler. This can lead to the patient getting significantly less than the prescribed amount of the active agent upon each activation of the Aerosol Inhaler. Coating the inner surface of the container with a suitable polymer can reduce this adhesion problem. Suitable coatings include, but are not limited to, fluorocarbon copolymers such as FEP-PES (fluorinated ethylene propylene and polyethersulphone) and PFA-PES (perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene.
Also, during storage, moisture can enter the Aerosol Inhaler mainly through the crimped area of the valve and through the stem by diffusion. To reduce the amount of moisture entering the Aerosol Inhaler, the metering valve is suitably comprised of a butyl Elastomer.
Each filled canister is conveniently fitted into a suitable actuator for administration of the medicament into the lungs of a patient. . Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or "puff.
Administration of medicament may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular particulate medicament used and the frequency of administration and will ultimately be at the discretion of the attendant physician. When combinations of medicaments are employed the dose of each component of the combination will in general employed for each component when used alone. Typically, administration may be one or more times, for example from 1 to 8 times per day, giving for example 1,2,3 or 4 puffs each time.
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Suitable daily doses, may be, for example in the range 25 to 200 microgram of salmeterol, 100 to 1000 microgram of salbutamol, 20 to 40 micrograms of Ipratropium, 50 to 2000 microgram of fluticasone propionate , 3 to 50 meg of Formoterol ,25 to 1000 meg of Budesonide , 5 - 500 meg of Fenoterol, 1.5 to 200 meg of Tiotropium bromide or 100 to 2000 microgram of beclomethasone dipropionate and their combinations depending on the severity of the disease.
Thus, for example, each valve actuation may deliver 25 microgram salmeterol, 100 microgram salbutamol, 25, 50, 125 or 250 microgram fluticasone propionate or 50, 100, 200 or 250 microgram beclomethasone Dipropionate, 20,40 meg of Ipratropium ,6,12 meg of Formoterol, 20,40 meg of Fenoterol ,9,18 meg of Tiotropium bromide. Typically each filled canister for use in a metered dose inhaler contains 50, 80, 100, 120, 160 or 240 metered doses or puffs of medicament.
The filled canisters and metered dose inhalers described herein comprise further aspects of the present invention.
A still further aspect of the present invention comprises a method of treating respiratory disorders such as, for example, asthma, which comprises administration by inhalation of an effective amount of a formulation as herein described.
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.
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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.
Formulation 1

Qty/can
Ipratropium Bromide monohydrate 5.04 mg
Salbutamol Sulfate 28.8 mg
PVPK25 20% (ofactive) 6.7 mg
Lactose 100% ( Of active) 33.8 mg
HFC-227 21 gm
Required quantity of PVP K 25 was weighed and dissolved in warm water to form a solution. Lactose was added to this solution and dissolved. Salbutamol Sulphate and Ipratropium Bromide monohydrate were added to the above solution to get a clear solution.
The solution so obtained was co-spray dried with inlet temperature of 105-110°C and outlet temperature of 55-60°C. The coated drug so obtained was then weighed in a suitable metal canister, crimped with a suitable valve and charged with HFC 227 Propellant
Formulation 2

Qty/can
Formoterol Fumarate 2.0 mg
PVP K 25 20% (of active) 0.4 mg
Lactose 100% ( Of active) 2.0 mg
HFA-227 21.2 gm
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Process:
Required quantity of PVP K 25 was weighed and dissolved in warm water to form a
solution. Lactose was added to this and dissolved. Formoterol fumarate was added to
the above solution to get a clear solution.
The solution so obtained was co-spray dried with inlet temperature of 105-110°C and
outlet temperature of 55-60°C. The coated drug so obtained was then weighed in a
suitable metal canister, crimped with a suitable valve and charged with HFC 227
Propellant
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, and the like.
Dated this 20th day of October 13, 2006

Dr. Gopakumar G. Nair Agent for the Applicant
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