WO2009050726A2

WO2009050726A2 - Compositions and methods for improved delivery of bupropion

Info

Publication number: WO2009050726A2
Application number: PCT/IN2008/000337
Authority: WO
Inventors: Amarjit Singh; Sarabjit Singh; Korlakunte Prasad; Rajesh Jain
Original assignee: Panacea Biotec Limited
Priority date: 2007-05-28
Filing date: 2008-05-28
Publication date: 2009-04-23
Also published as: WO2009050726A3

Abstract

The present invention provides a pharmaceutical composition comprising micronized bupropion having controlled particle size in the range between 1-60 μm. The pharmaceutical composition of the present invention comprises micronized bupropion having median particle size less than 40 micron, which exhibits outstanding bioavailability via nasal and pulmonary route even without any need for blending the micronized bupropion with large carrier particles. The composition of the present invention comprises micronized bupropion -and one or more pharmaceutically acceptable carriers, surfactants, a dispersing agents, or dispersants, which can be administered in an aerosol formulation as a dry powder for nasal and pulmonary inhalation. Particularly, the composition of the present invention for nasal delivery comprises bioadhesive microparticles of bupropion and carbohydrates like pullulan to prevent and treat diseases such as depression, premenstrual syndrome, premature ejaculation and as an aid to smoking cessation. The invention also provides a process of preparing the compositions of the present invention.

Description

COMPOSITIONS AND METHODS FOR IMPROVED DELIVERY OF BUPROPION

FIELD OF THE INVENTION:

The present invention belongs to the field of pharmaceutical sciences. It provides new pharmaceutical composition, its preparation, use and method of administration for bupropion.

BACKGROUND OF THE INVENTION:

Bupropion hydrochloride, designated chemically as (±)-l-(3-chlorophenyl)-2-[(l,l- dimethylethyl)amino]-l-propanone hydrochloride, is an antidepressant drug. It is chemically unrelated to classical tricyclic, tetracyclic, selective serotonin re-uptake inhibitors or other known antidepressant drugs. It is a dopamine-specific atypical antidepressant of the aminoketone class. It is sold by Glaxo Wellcome under the brand names Wellbutrin^®, Wellbutrin^® SR and Wellbutrin^® XL for the treatment of depression. Glaxo Wellcome also has FDA approval to market sustained release formulation of bupropion hydrochloride as an aid to smoking cessation treatment, under the brand name Zyban®. Both Zyban® and Wellbutrin® SR are chemically and pharmaceutically identical.

The usual adult dose of Wellbutrin^® as immediate release formulation is 300mg/day administered 3 times daily, preferably with at least 6 hours between successive doses. For patients who require, dose more than 300 mg per day, each dose should not exceed 150 mg, thus requiring administration of four tablets (100 mg each) in a day with at least 4 hours between successive doses. With the progress of intensive research, modified release formulations of bupropion hydrochloride have been developed to minimize the risk of seizures which is one of the major adverse event associated with the immediate release of bupropion in the system. These include the sustained release products Wellbutrin^® SR and Zyban which are dosed twice daily; each dose not exceeding 150 mg and the extended release once-daily product Wellbutrin^® XL. But the labels of these, products indicate that seizure and adverse events like agitation, vomiting and others are still the cause of discontinuation of treatment in some patient.

The absolute bioavailability of an oral dose of bupropion in man has not been determined and is expected to be low. In rat and dog studies the bioavailability of bupropion ranged from 5 to 20%. Bupropion is absorbed from the gastrointestinal tract after oral administration and is extensively metabolized in rats and humans prior to excretion. Three principal metabolites, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion appear to have slower clearance than bupropion; therefore they tend to accumulate to a greater extent than the parent drug during chronic bupropion therapy. In antidepressant screening assay, the hydroxybupropion is one half as potent as bupropion while others are 5-fold less potent than bupropion. Furthermore, as mentioned above bupropion therapy is associated with seizures in approximately 0.4% of the patients treated with doses up to 450 mg/day. The incidence of seizures may exceed those of other antidepressants by up to four fold, increasing to approximately tenfold at doses of 450-600 mg/day. Oral administration of bupropion in general is known to result in numerous dose-dependent adverse side effects, including seizure, headache/migraine, insomnia, dry mouth, dizziness, excessive sweating, anorexia, weight loss, constipation, sedation, tremor, and agitation.

Thus there exists a need to develop a composition with improved physicochemical and/or biological property for bupropion and or its pharmaceutically acceptable salts or its derivatives. There is a need to provide a bupropion composition with high bioavailability, lower dose and reduced side- effect profile. All this also leads to the requirement of providing a safe and convenient method of administering bupropion at a safe and effective dose.

Apart from oral administration, inhalation is one of the safe and convenient methods of administering drug to patients, which is widely used for the delivery of small and large molecules to the nasal cavity or lung. There are number of small molecules that are delivered via inhalation which are available in the market, most notably beta-androgenic antagonist, corticosteroids and cromolyn sodium to treat asthma and also there is large molecule like insulin, (See EXUBARA), which is available as inhalation to be administered through lung for systemic absorption However, not all small and large molecules can be effectively administered through the lung. In some cases, drugs are unable to pass into blood stream through alveolar epithelium while in other cases; drugs are found to be irritating and broncho-constrictive in nature. Thus, it is not possible to predict the bio-availability^ of a molecule and it requires extensive research and experimentation to formulate a composition for effective administration via inhalation route.

There is very less information available on nasal or pulmonary administration of anti-depressant drugs and no experimental data available on improved delivery of bupropion by administering via nasal or pulmonary route and method of treatment and prophylaxis of disease comprising administration of bupropion by inhalation.

United States Patent No. 6,979,437 relates to methods of treating disorders of the central nervous system by delivering a drug to the pulmonary system especially to the alveoli or the deep lung. The drug or medicament is included in the particles that are employed for respiratory tract administration along with other materials such as for example phospholipid, amino acids, combination thereof and others. The drug or medicament mainly employed to describe the methods of the invention is a dopamine precursor or a dopamine agonist i.e. levodopa (L-DOPA). No antidepressant has been described in this invention.

United States Patent No. 6,783,753 discloses composition for the delivery of anti-depressants comprising condensation aerosol which comprises three elements: an element for heating an antidepressant containing composition to form a vapor; an element for allowing the vapor to cool, thereby providing a condensation aerosol; and, an element permitting the mammal to inhale the aerosol. However this method involves the use of energy in the form of heat to vaporize the drug and then condense in the form of fine particles. Use of such a method for thermally sensitive drugs such as bupropion is not desirable.

The inventors of the present invention have found means of improving delivery of bupropion and improving bioavailability of bupropion. The inventors have found that bupropion has substantially improved systemic plasma concentration and hence bioavailability when delivered via pulmonary route when compared to oral route.

SUMMARY OF THE INVENTION

The present invention provides the pharmaceutical composition of bupropion comprising merely micronized bupropion having controlled particle size in the range between 1-60 μm.

The present invention provides a pharmaceutical composition comprising micronized bupropion having median particle size less than 40 micron, which elicits improved bioavailability through any route of administration like oral, nasal, pulmonary, injectable, vaginal and others. In one of the aspect, the present invention provides a pharmaceutical composition of micronized bupropion which elicits improved bioavailability via inhalation which includes nasal or pulmonary route of administration.

Another aspect of the invention is to provide the pharmaceutical composition of bupropion comprising micronized bupropion hydrochloride and one or more pharmaceutically acceptable carriers, surfactants, dispersing agents, or dispersants, which can be administered in an aerosol formulation as a dry powder or as a solution or suspension form.

Another aspect of the invention is to provide the dry powder composition of bupropion for inhalation comprising micronized bupropion and pharmaceutically acceptable carriers.

Another aspect of the invention is to provide the dry powder composition of bupropion for pulmonary inhalation comprising micronized bupropion and pharmaceutically acceptable carriers.

It is yet another aspect of the invention to provide the dry powder composition of bupropion for nasal delivery comprising micronized bupropion and pharmaceutically acceptable carriers.

It is yet another aspect of the invention to provide the dry powder composition of bupropion for inhalation comprising micronized bupropion and surfactant.

It is yet another aspect of the invention to provide the dry powder composition of bupropion for nasal or pulmonary inhalation comprising micronized bupropion and surfactant, wherein surfactant is dipalmitoyl phosphatidylcholine.

It is yet another aspect of the invention to provide the dry powder composition of bupropion for nasal delivery comprising bioadhesive microparticles of bupropion and bioadhesive carrier, wherein the preferred carrier is polysaccharide like pullulan.

Yet another aspect of this invention is a method of administering a therapeutically effective amount of the dry powdered composition of this invention to a human subject in need thereof by dispersing said powdered composition as an aerosol into a chamber having a delivery outlet suitable for inhalation therapy, e.g., a mouthpiece and having said subject inhale via nasal or oral route said dispersed powder into the subject's lungs.

Another aspect of this is to provide method of preparing dispersible dry powder composition that comprises micronized bupropion and optionally pharmaceutically acceptable carrier (s) or surfactant to improve the aerosolozation of the powder composition by inhalation.

Another aspect of this invention is a method for preparing a spray-dried, dispersible powdered pharmaceutical composition that comprises spray drying a homogeneous aqueous mixture comprising physiologically acceptable solvent, micronized bupropion for inhalation and optionally pharmaceutically acceptable carrier (s) or surfactant to provide a dispersible powdered pharmaceutical composition having a particle size less than about 40 microns.

DETAILED DESCRIPTION

Before describing the invention in detail, it is to be understood that this invention is not limited to the particular systems, process steps, and materials disclosed herein as modification to these may occur to a person skilled in the art. It is also to be understood that the terminology employed herein is used for the purpose of describing particular aspects only and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

It must be noted that as used in the specification and the appended claims, the singular forms 'a', 'an' and 'the' include plural references unless the context clearly indicates otherwise.

The terms used in the present specification are explained below:

The "micronized bupropion" means powders of bupropion having a median (d₅₀) particle size of less than about 40 μm, preferably less than about 30 μm. The "median particle size" or ds₀ represents the cumulative distribution of particle size such that 50% (by weight or volume basis) of the particles are smaller than or equal to the said size. The term "about" is used with the intention of including values following said term. The term "bupropion" refers to either (R)-bupropion, (S)-bupropion or a racemic mixture of (R)- and (S)-bupropion. According to this invention, bupropion may be administered either as a free base or in the form of a pharmaceutically acceptable salt thereof. In a particularly preferred aspect, the pharmaceutically acceptable salt is bupropion HCl.

The term 'about' with respect to the composition can mean plus or minus a range of up to 20%, preferably up to 10%, more preferably up to 5%. Where particular values are described in the application and claims, unless otherwise stated the term "about" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art.

The term "dry powder" refers to a composition that contains finely dispersed solid particles that are capable of (i) being readily dispersed in or by means of an inhalation device and (ii) inhaled by a subject so that a portion of the particles reach to the nasal cavity or the lungs. Such a powder is considered to be "respirable" or suitable for pulmonary delivery. A dry powder typically contains less than about 15% moisture, preferably less than 11% moisture, and more preferably contains less than about 8% moisture.

The term "emitted dose" or "ED" refers to an indication of the delivery of dry powder from a suitable inhaler device after a dispersion event from a powder unit, capsule, or reservoir. ED is defined as the ratio of the dose delivered by an inhaler device to the nominal dose (i.e., the mass of powder per unit dose placed into a suitable inhaler device prior to dispersion). The ED is an experimentally-determined amount, and is typically determined using an in-vitro device set up which mimics patient dosing. To determine an ED value, a nominal dose of dry powder (as defined above) is placed into a suitable dry powder inhaler, which is then actuated, dispersing the powder. The resulting aerosol cloud is then drawn by vacuum from the device, where it is captured on a tared filter attached to the device mouthpiece. The amount of powder that reaches the filter constitutes the delivered dose. For example, for a 5 mg, dry powder-containing blister pack placed into an inhalation device, if dispersion of the powder results in the recovery of 4 mg of powder on a tared filter as described above, then the ED for the dry powder composition is: 4 mg (delivered dose)/5 mg (nominal dose)^χ 100=80%.

As used herein, the term "mass median aerodynamic diameter" or "MMAD" is a measure of the aerodynamic size of a dispersed particle. The aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior, and is the diameter of a unit density sphere having the same settling velocity, generally in air, as the particle. The aerodynamic diameter encompasses particle shape, density and physical size of a particle. As used herein, MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by Anderson cascade impaction.

As used herein, the term "pharmaceutically acceptable excipient or carrier" refers to an excipient that can be taken into the nasal cavity or lungs in association with micronized bupropion' with no significant adverse toxicological effects to the subject, and particularly to the nasal cavity or lungs of the subject. The said term collectively used as carriers in this invention.

As used herein, the term "side effects associated with bupropion therapy" refers to undesirable effects suffered by a patient including, but not limited to, seizure, headache/migraine, insomnia, dry mouth, dizziness, excessive sweating, anorexia, weight loss, constipation, sedation, tremor, and agitation and is further intended to include development of resistance to bupropion therapy.

The present invention provides a pharmaceutical composition comprising micronized bupropion which elicits improved bioavailability over the composition comprising conventional bupropion. According to the present invention, compositions and methods for the administration of micronized bupropion for the prevention and/or treatment of the diseases such as depression, premenstrual syndrome, premature ejaculation. Furthermore, it can be useful as an aid to smoking cessation treatment. The composition of the present invention is also useful to treat other diseases for which bupropion is found to be useful.

The high oral dose of bupropion is required for therapeutically effective treatment, while the micronized bupropion shows therapeutic effect at low dose. The micronized bupropion of the present invention exhibits outstanding bioavailability via inhalation even without any need for blending the micronized bupropion with large carrier particles.

In an important aspect of the present invention, it has been surprisingly found that the systemic absorption or bioavailability of the bupropion from the composition can be remarkably improved by using micronized bupropion and optionally by further inclusion of suitable type, amount and particle size ratios of pharmaceutical excipients or carriers. One aspect of this invention is to provide the pharmaceutical composition of bupropion comprising merely micronized bupropion having controlled particle size in the range between 1-60 μm. The particles are such that the median particle size is less than 40 micron.

The present invention provides a pharmaceutical composition comprising micronized bupropion having median particle size less than 40 micron, which elicits improved bioavailability through any route of administration like oral, nasal, pulmonary, injectable, vaginal and others.

Another aspect of the invention is to provide the pharmaceutical composition of bupropion comprising micronized bupropion hydrochloride and one or more pharmaceutically acceptable carriers, surfactants, dispersing agents or dispersants, which can be administered in an aerosol formulation as a dry powder or as a solution or suspension form. In a preferred aspect of the invention, the composition is a dry powder for inhalation, which includes the nasal or pulmonary route of administration.

The pharmaceutical compositions of the present invention may be in the form of particles, powders, granules, pellets, capsules, tablets etc to be delivered by suitable route of administration.

Another aspect of the invention is to provide the dry powder composition of bupropion comprising micronized bupropion and pharmaceutically acceptable carriers.

It is yet another aspect of the invention to provide the dry powder composition of bupropion comprising micronized bupropion and surfactant.

It is yet another aspect of the invention to provide the dry powder composition of bupropion for nasal delivery comprising micronized bupropion and pharmaceutically acceptable carriers wherein pharmaceutically acceptable carriers is dispersed homogeneously with bupropion or coated onto said bupropion particles. The carrier of the present invention comprises a physiologically acceptable powdery or crystalline carrier, whose mean particle size is in the range of about 20 to about 350 μm, more preferably in the range of about 20 to about 100 μm. It is yet another aspect of the invention to provide the dry powder composition of bupropion for nasal delivery comprising bioadhesive microparticles of bupropion and carrier like carbohydrates such as pullulan to prevent and treat diseases such as depression, premenstrual syndrome, premature ejaculation and as an aid to smoking cessation treatment. The nasal administrable compositions of the present invention may further optionally comprise one or more other adjuvants.

The improved bioavailability of micronized bupropion is demonstrated in the present invention by administering bupropion via nasal or pulmonary route. Thus the present invention also provides composition and method for safely and conveniently administering bupropion to a patient in need of treatment comprising inhalation of a therapeutically effective amount of bupropion to prevent and treat diseases such as depression, premenstrual syndrome, premature ejaculation and as an aid to smoking cessation treatment. The composition of the present invention is also useful to treat other diseases for which bupropion is found to be useful.

The dry powder composition comprises of the particles of micronized bupropion and pharmaceutically acceptable carriers which are suitable for respiratory, pulmonary and nasal administration. Such carriers may serve simply as bulking agents when it is desired to reduce the active agent concentration in the powder which is being delivered to a patient. Such carriers may also serve to improve the dispersibility of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the active agent and to improve the handling characteristics of the active agent (e.g., flowability and consistency) to facilitate manufacturing and powder filling. In particular, the carrier materials can often function to improve the physical and chemical stability of the micronized bupropion, to minimize the residual moisture content and hinder moisture uptake, and to enhance particle size, degree of aggregation, surface properties (i.e., rugosity), ease of inhalation, and targeting of the resultant particles to the deep lung when administered by pulmonary route.

The pharmaceutically acceptable carriers used in this invention may be micronized, non-micronized or mixture thereof. Pharmaceutical carriers used in the composition of the present invention include but are not limited to proteins, peptides, amino acids, lipids, polymers, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, terra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which may be present singly or in combination. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/polypeptide components, which may also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, proline, isoleucine, valine, methionine, phenylalanine, aspartame, and combination thereof. Polyamino acids of the representative amino acids such as di-leucine and tri-leucine are also suitable for use with the present invention. One preferred amino acid is leucine. Other pharmaceutical excipients and/or carriers suitable for use in the micronized bupropion dry powder compositions according to the invention are listed in "Handbook of Pharmaceutical Excipients ", 5^th ed, Raymonds C Rowe, Paul J Sheskey and Sian C Owen.

Carbohydrate excipients suitable for use in the invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and combination thereof; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and combination thereof; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myoinositol and combination thereof. The preferred carrier of the present invention is lactose used in the range of from about 1.0 % w/w to 95% w/w.

Furthermore, the starch component of pharmaceutically acceptable carrier used in the present invention includes corn starch, potato starch, rice starch, glutinous rice starch, wheat starch, pregelatinized starch, dextrin, sodium carboxymethyl starch, hydroxypropyl starch, pullulan and the like.

Pullulan is a polysaccharide polymer consisting of maltotriose units, also known as a- 1,4- ;a-l,6- glucan. Three glucose units in maltotriose are connected by an a- 1,4 glycosidic bond, whereas consecutive maltotriose units are connected to each other by an a- 1,6 glycosidic bond. Pullulan is produced from starch by the fungus Aureobasidium pullulans. Available as a white powder it is odorless, flavorless, and highly stable. Pullulan is a neutral glucan (like Amylose, Dextran, Cellulose), with a chemical structure somewhat depending on carbon source, producing microorganism (different strains of Aureobasidium pullulans), fermentation conditions. Pullulan has about double the adhesive strength of food starch. In preferred aspect of the present invention pullulan is added in an amount ranging from about 1.0% w/w to about 30% w/w. A more preferred aspect comprises micronized bupropion and pullulan wherein bupropion is present in an amount ranging from about 0.1% w/w to about 50.0% w/w and pullulan is present in an amount ranging from about 1.0% w/w to about 30.0% w/w

Preferred pharmaceutically acceptable carriers are bioadhesive carriers which includes and are not limited to the said carbohydrates like pullulan, carrageenan, locust bean gum, gellan gum, xanthan gum, pectin, dextran and others and derivatives and combinations thereof.

The dry powder composition of the present invention may also include a buffer or a pH adjusting agent. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, phosphate buffers or combination thereof.

Surfactants used in this invention can be incorporated into particles to improve their aerosolization properties include phosphoglycerides. Exemplary phosphoglycerides include phosphatidylcholines, such as the naturally occurring surfactant, dipalmitoyl phosphatidylcholine ("DPPC"), included in preferred aspect of the present invention in the range of about 1.0% w/w to about 40% w/w. The surfactants advantageously improve surface properties by, for example, reducing particle-particle interactions, and can render the surface of the particles less adhesive. The use of surfactants endogenous to the lung may avoid the need for the use of non-physiologic surfactants. Surfactants generally possess a hydrophilic moiety and a lipophilic moiety; such that, upon absorbing to microparticles, they tend to present moieties to the external environment that do not attract similarly-coated particles, thus reducing particle agglomeration. Surfactants may also promote absorption of a therapeutic or diagnostic agent and increase bioavailability of the agent.

The surfactant may be incorporated throughout the particle and on the surface during particle formation, or may be coated on the particle after particle formation. The surfactant can be coated on the particle surface by adsorption, ionic or covalent attachment, or physically "entrapped" by the surrounding matrix. The surfactant can be, for example, incorporated into controlled release particles, such as polymeric microspheres. Surfactants known in the art can be used including any naturally occurring surfactant. Other exemplary surfactants include diphosphatidyl glycerol (DPPG); hexadecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid; sorbitan trioleate (Span 85); glycocholate;surfactin; a poloxomer; a sorbitan fatty acid ester such as sorbitan trioleate; tyloxapol and a phospholipid.

According to the present invention, a dispersing agent for improving the intrinsic dispersibility properties of the micronized bupropion powders is added. Suitable agents are disclosed in PCT applications WO 95/31479, WO 96/32096, and WO 96/32149, hereby incorporated in their entirety by reference. As described therein, suitable agents include water soluble polypeptides and hydrophobic amino acids such as tryptophan, leucine, phenylalanine, and glycine. Leucine and tri- leucine are particularly preferred for use according to this invention.

Additionally, the micronized bupropion dry powders of the invention may include polymeric carriers such as polyvinylpyrrolidones, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, Ficolls (a polymeric sugar), dextran, dextrates (e.g., cyclodextrins, such as 2- hydroxypropyl-β-cyclodextrin, hydroxyethyl starch), polyethylene glycols, pectin, flavoring agents, salts (e.g. sodium chloride), antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and "TWEEN 80", lecithin, oleic acid, benzalkonium chloride, and sorbitan esters), lipids (e.g., phospholipids, fatty acids ), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA). Exemplary surfactants include naturally occurring phophatidylcholine, such as dipalmitoylphosphatidylcholine ("DPPC"). In a preferred aspect the dry powder composition for inhalation of the present invention is such that the micronized bupropion is coated with dipalmitoylphosphatidylcholine wherein bupropion is present in an amount ranging from about 0.1% w/w to about 50.0% w/w and dipalmitoylphosphatidylcholine is present in an amount ranging from about 1.0% w/w to about 40.0% w/w.

The polymers used in the composition of the present invention includes but not limited to polyanhydrides such as poly[(p-carboxyphenoxy)-hexane anhydride] (PCPH), polyglycolic acid (PGA), polylactic acid (PLA), or copolymers thereof. Other polymers include polyamides, polycarbonates, polyalkylenes such as polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly vinyl compounds such as polyvinyl alcohols, polyvinyl ethers, and polyvinyl esters, polymers of acrylic and methacrylic acids, celluloses and other polysaccharides, and peptides or proteins, or copolymers or blends thereof. Polymers may be selected with or modified to have the appropriate stability and degradation rates in vivo for different controlled drug delivery applications.

Polymeric particles may be prepared using single and double emulsion solvent evaporation, spray drying, solvent extraction, solvent evaporation, phase separation, simple and complex coacervation, interfacial polymerization, and other methods well known to those of ordinary skill in the art. Particles may be made using methods for making microspheres or microcapsules known in the art, provided that the conditions are optimized for forming particles with the desired aerodynamic diameter, or additional steps are performed to select particles with the density and diameter sufficient to provide the particles with an aerodynamic diameter between one and five microns, preferably between one and three microns.

Materials other than biodegradable polymers may be used to form the particles. Suitable materials include various non-biodegradable polymers and various excipients. The particles also may be formed of micronized bupropion and surfactant alone. In one of the aspect, the particles may be formed of the surfactant and micronized bupropion, to improve aerosolization efficiency due to reduced particle surface interactions, and to potentially reduce loss of the agent due to phagocytosis by alveolar macrophages.

The composition of this invention may be delivered from a unit dosage receptacle comprising an amount that is sufficient to provide the desired physiological effect upon inhalation by a subject in need thereof. The amount is dispersed in a chamber that has an internal volume sufficient to capture substantially all of the powder dispersion resulting from the unit dosage receptacle.

Usually the volume of the chamber will be from about 50 ml to about 1000 ml, preferably from about 100 ml to about 750 ml. Thus, the unit dosage amount will be from about 2 mg of powder to about 20 mg of powder preferably about 4 mg to about 10 mg of powder per unit dosage. About 5 mg per unit dosage is quite effective. Thus, therapeutic plasma concentrations of bupropion, following pulmonary administration may be achieved at lower doses as compared to oral administration. Preparation of dry powder composition of micronized bupropion

The dry powder composition of micronized bupropion is prepared by using various methods viz milling, spray drying, vacuum drying, spray-freeze drying, super-critical fluid techniques, precipitation or any other method known in the art. All other methods known from standard textbooks and research articles for micronization of a material to form powders of desired particle size is also inclusive within the scope of this specification and can be utilized for the purpose of this invention.

In one of the aspect, dry powder composition of the present invention is prepared by milling that is conventionally used in the pharmaceutical field. Mills are, for example, a fluid energy mill such as Jet mill, a high speed rotative impact mill such as Sample mill, Pin mill or Angmill, a wet form high speed tumbling trituration mill or a tumbling mill such as a Ball mill. In order to obtain micronized powders having a median particle size of less than about 20 μm or 10 μm or 5 μm, a fluid energy mill is preferably used. In order to minimize or avoid static charges encountered during milling process of bupropion alone and to improve its handling properties the micronization of bupropion^' can be carried out on a mixture of bupropion and a part or whole of pharmaceutical excipients or carriers, which are used in the preparation of pharmaceutical compositions.

Control of particle size is also achieved by the technique of spray drying of the drug alone or . in combination with pharmaceutical stabilizers. Spray drying techniques and process to be used are well known in the art and can be utilized for the purpose of this invention. In another aspect of the invention, dry powder composition of bupropion is prepared by spray-drying the bupropion containing solution. The bupropion containing solution is prepared by dissolving bupropion in physiologically acceptable solvent such as water having a pH in range of 3 to 10, preferably 5 to 8. The aqueous solution may optionally comprise water-miscible solvents such as alcohols, acetone and the like. Representative alcohols are methanol, ethanol, propanol, isopropanol, butanol and the like. The bupropion containing solutions are then spray-dried in a conventional spray drier. The aqueous solution of bupropion may comprise additionally surfactant described herein. In an aspect the dry powder composition for inhalation by either nasal or pulmonary route of the present invention comprises a blend of micronized bupropion and lactose wherein the lactose is present in the form of micronized lactose and coarse lactose or sieved fraction of lactose. The lactose is generally present in the particle size range of about 20 μm to about 350 μm. In another aspect of the present invention, dry powder composition of bupropion is prepared by spray-drying the bupropion containing lipid suspension. The bupropion containing lipid suspension is prepared by dissolving surfactant in water-miscible solvents which is then added to another solvent to form emulsion which result into solid fine suspension of surfactant. Bupropion (micronized or non-micronized) is added into suspension of surfactant in acetone. The bupropion containing lipid suspension is then spray-dried in a conventional spray drier.

In yet another aspect of the present invention, dry powder composition of bupropion is prepared by spray-drying the bupropion containing polymer solution. The bupropion containing polymer solution is prepared by dissolving the polymer like pullulan along with other excipients and/or carriers which includes gums in a suitable solvent like water. Bupropion (micronized or non- micronized) is added into the above solution which is then spray-dried in a conventional spray drier.

Bupropion Dry Powder Characteristics

The physical characteristics of the bupropion dry powder composition described herein are important in maximizing the efficiency of aerosolized delivery of such composition to the nasal cavity or the lung.

The bupropion dry powders are composed of particles of micronized bupropion and optionally one or more pharmaceutical acceptable carriers or surfactant which is effective to penetrate into the lungs, having median particle size less than about 40 μm, preferably less than 30 μm, and most preferably less than 25 μm. Preferred powders are composed of particles having median particle size from about 0.5 to 20.0 μm.

The bupropion powders of the invention are further characterized by an aerosol particle size distribution less than about 10 μm mass median aerodynamic diameter (MMAD), and preferably less than 5.0 μm. The mass median aerodynamic diameters of the powders will characteristically range from about 0.5-10 μm, preferably from about 0.5-5.0 μm MMAD, more preferably from about 1.0-4.0 μm MMAD. The bupropion dry powders generally have moisture content below about 15% by weight, usually below about 11% by weight, and preferably below about 8% by weight. The moisture content of representative bupropion dry powders prepared as described herein is provided in the Examples.

The emitted dose (ED) of these powders is greater than 50%. More preferably, the ED of the bupropion powders of the invention is greater than 70%, and is often greater than 80%. In looking at the Examples, it can be seen that applicants have successfully prepared a large number of representative bupropion dry powders with ED values greater than or equal to 80%.

Pulmonary Administration of the Composition

Pulmonary or respiratory tract administration of bupropion can be achieved by directing the stream of therapeutically effective amount of micronized bupropion hydrochloride into the oral cavity of the patient in need of treatment to inhale. Surprisingly it was discovered that the therapeutically effective amount of bupropion got deposited into the lung and was rapidly absorbed from the lung into the bloodstream, resulting in elevated blood levels of bupropion. Thus, therapeutic plasma concentrations of bupropion, following pulmonary administration may be achieved at lower doses as compared to oral administration.

Delivering the composition of micronized bupropion described herein by inhalation can be achieved by means known in the art. Various suitable inhaler devices and methods of inhalation which can be used to administer the composition of bupropion to a patient's respiratory tract are known in the art. For example, suitable inhalers are described in U.S. Pat. No. 4,069,819, issued Aug. 5, 1976 to Valentini, et al., U.S. Pat. No. 4,995,385 issued Feb. 26, 1991 to Valentini, et al., and U.S. Pat. No. 5,997,848 issued Dec. 7, 1999 to Patton, et al. Other examples include, but are not limited to, the Spinhaler®) (Fisons, Loughborough, U.K.), Rotahaler® (Glaxo-Wellcome, Research Triangle Technology Park, North Carolina), FlowCaps® (Hovione, Loures, Portugal), Inhalator® (Boehringer-Ingelheim, Germany), and the Aerolizer (Novartis, Switzerland), the Diskhaler (Glaxo- Wellcome, RTP, NC) and others, such as known to those skilled in the art.

The invention has been described and illustrated herein by various specific materials, formulations, procedures and examples, it is understood that the invention is not restricted to the particular material, combinations of material, and procedures selected for that purpose. Numerous variations of such details can be implied and will be appreciated by those skilled in the art.

Examples:

1. Preparation of micronized or Jet milled formulation of bupropion

Bupropion HCl was micronized using an air jet mill (Labomill, 204, Food Pharma Systems, Italy). Particle size of micronized bupropion was measured using, laser diffraction technique (Horiba -LA 950 particle size analyzer, Japan). Micronized bupropion had median particle size below 5μm. Tap density of the micronized bupropion was measured using a tap density tester, USP (Electrolab, India, model no. ETD 1020) micronized bupropion had a tap density value of about 0.28g/cm³. Residual moisture content was measured using Metrohm Coulometer 83 IF and Thermoprep 832, and a residual moisture content value of about 0.21% w/w.

2. Preparation of binary blend formulation containing micronized bupropion and coarse lactose

Micronized bupropion was blended with coarse lactose carrier particles. 4g of Respitose SV003 (DMV international Pharma, The Netherlands) lactose was mixed with 1 g of micronized bupropion in a closed glass vial for 15 minutes. Then the blend was passed through 150 μm sieve. The screened blend was re-blended for 15 minutes. The content uniformity of composition was assayed using UV or HPLC method.

3. Preparation of tertiary blend formulation containing micronized bupropion, micronized lactose and coarse lactose

20gms of Pharmatose DCL 22 lactose was micronized using an air jet mill. Median particle size of the micronized lactose, measured using laser diffraction technique, was less than 10 μm.

3.6g of Respitose SV003 was mixed with 0.4 grams of micronized DCL22 in a glass vial for 15mins. Then the blend was passed through 150 μm sieve. The screened blend was re-blended for 15minutes. 4g blend of micronized lactose and coarse lactose was mixed with Ig of micronized bupropion in a glass vial for about 15minutes. Then the blend was passed through 150 μm sieve. The content uniformity of composition was assayed using UV or HPLC method. 4. Preparation of tertiary blend formulation containing micronized bupropion, micronized lactose and sieved fraction of lactose

Sieved fraction of Respitose SV003 lactose was obtained by sieving the lactose by passing the bulk material through 45 μm sieve. The particle size of the sieved fraction was measured using particle size analyzer. The median size of the sieved fraction of the lactose was about 61 μm.20gms of Pharmatose DCL 22 lactose was micronized using an air jet mill.

3.6g of sieved fraction of SV003 was mixed with 0.4 grams of micronized DCL22 in a glass vial for 15mins. Then the blend was passed through 150 μm sieve. The screened blend was re-blended for 15minutes. 4g blend of micronized lactose and coarse lactose was mixed with Ig of micronized bupropion in a glass vial for about 15minutes. Then the blend was passed through 150 μm sieve. The content uniformity of composition was assayed using UV or HPLC method.

5. Preparation of dipalmitoyl phosphatidylcholine(DPPC) coated spray dried bupropion formulations

Due to high static charge, the micronised particles tend agglomerate and form cohesive powder. In order to remove the static charge on the micronised bupropion particles and to decrease the cohesiveness of the powder, micronised bupropion was suspended in a lipid suspension and subsequently spray dried. 100- 400mg of DPPC (Lipoid GMBH, Germany) was solubilized in ethanol. Then DPPC solution was added drop-wise to acetone to form emulsion. DPPC forms solid fine suspension in acetone. 2grams of micronised drug was added to the DPPC suspension in acetone while sonicating. The bupropion and lipid suspension was spray dried. The spray dried formulation was less cohesive and had less static charge compared to pure jet milled bupropion. The yield was 53-68%. The spray dried lipid coated bupropion formulation showed decreased cohesiveness.

Particle analysis of micronised bupropion was characterized using Horiba -LA 950, laser diffraction technique., Tap density of the micronised bupropoin was measured using a Tap density tester,USP , Electrolab, India (model no. ETD 1020). Residual moisture content was measured using Metrohm Coulometer 83 IF and Thermoprep 832. 6. Filling of formulation into capsules

5mg (without lactose carrier) or 25mg (with lactose carrier) of formulation was filled manually into size 3, HPMC capsules (Associated Capsules Pvt. Ltd., India). Filled HPMC capsules were stored in a desiccator till further analysis.

7. Tap Density Testing

The tap density (TD) of the bupropion formulations mentioned above was measured using a standard microprocessor controlled Tap density tester, USP. The powder formulation was filled in a graduated measuring cylinder (5 ml or 10ml capacity) and tapped for about 1000 taps which allowed the density to plateau. The results of which are given in Table 1.

8. In vitro aerosol deposition testing using Anderson Cascade Impactor

Aerodynamic assessment of fine particles were measured using Copley' Anderson Cascade Impactor (8 Stage Cascade Impactor, Copley Instruments, UK). Previously filled capsules of all the examples above were placed in an Aerolizer® inhaler (Novartis Pharma AG, Switzerland). The capsule was then pierced; the liberated powder was drawn through the 6OL conversion kit impactor, operating at flow rate of lOOL/min (at sonic flow) for 2.4s. The amount of powder deposited on the different stages of the impactor was recovered and analyzed using UV or HPLC method. The powder deposited in the throat and the pre-separator was also collected and analyzed.

The emitted dose (ED) was determined as the total powder mass exiting the capsule. The cumulative mass of the powder less than the stated size of each stage of the Anderson cascade impactor was calculated and plotted on a log probability graph as percent of total mass recovered in the impactor against the aerodynamic diameter (effective cut off diameter). According to the US Pharmacopeia (US Pharmacopeia, <601>, 1999, Aerosols, metered dose inhalers and dry powder inhalers, 4933-4949), the experimental MMAD (mass median aerodynamic diameter) of the particles is defined from the graph as the particle size at which the line crosses the 50% mark and the geometric standard deviation (GSD) as (GSD = (size at 84%/size at 16%)^1/2). The fine particle fraction (FPF) was calculated by interpolation from the same plot as the fraction of powder emitted from the inhaler with an aerodynamic diameter size < 5μm. Table 1 gives the "Aerosolization Characterization- Anderson Cascade Impactor data" and the Tap Density data obtained for the samples tested.

* Median diameter - Drug Particles size

NFW = Nominal Fill Weight

ND = Nominal Dose (drug content/dose)]

Table 2 further provides "Aerosolization Characterization- Anderson Cascade Impactor data" in terms of mass fraction content at each stage of impactor which determines the efficiency of aerosolization of the dry powder composition during inhalation.

9. Preparation of composition for delivery into the nasal cavity

Micronized bupropion for nasal administration is prepared by using air jet mill (Labomill, 204, Food Pharma Systems, Italy) with a feeder with very slow rate. Particle size of micronized bupropion was measured using, laser diffraction technique (Horiba -LA 950 particle size analyzer, Japan). Micronized bupropion for nasal administration had median particle size d₅o below 30 μm. 10. Preparation of blend for delivery into nasal cavity:

The micronized bupropion was blended with Lactohale LH 100 lactose (Fries land-Neither lands) whose particle size was D10=67.7 μm, D50=138.39 μm, D 90 =284.53 μm., mixing of blend was done manually in a screw cap glass vial and sifted through 250 μm sieve and the process was repeated again.

11. Preparation of dipalmitoyl phosphatidylcholine (DPPC) coated spray dried bupropion formulations for nasal delivery

200 mg Dipalmitoylphosphatidylcholine (DPPC) was solubilized in ethanol. Then DPPC/ethanol solution was added to acetone while probe sonicating at 50 amplitude and continuous sonication. Opaque solution was formed, to this solution 2 gm micronized Bupropion HCl was added while bath sonicating and dispersed. The suspension formed was then spray dried while stirring.

12. Preparation of bioadhesive microparticles bupropion and pullulan

(a) 10 % Pullulan, 0.45 % Glycerine, 0.45% Sorbitol, 0.045 % Carrageenan and 0.045% locust bean gum was dissolved in 75.8 g of water .To the above solution Bupropion HcI was solubilized and spray dried.

(b) 10 % Pullulan, 0.45 % Glycerine, 0.45% Sorbitol, 0.045 % Carrageenan and 0.045% locust bean gum was dissolved in 75.8 g of water .To the above solution Bupropion HCl was solubilized and sprayed with ultra sonic nozzle in to liquid nitrogen and after complete spray of the solution in to the liquid nitrogen, it was kept aside to evaporate the liquid nitrogen to some extent and then freeze drying was carried out for 24 hrs.

13. Determination of plasma concentrations of bupropion after pulmonary administration and comparison to the plasma concentrations after oral administration

Wistar rats (350-400 g), n=7/group were taken for studying pharmacokinetics of micronized bupropion sample by pulmonary and oral route. Under anesthesia micronized Bupropion HCl was administered to pulmonary grouped rats (Group 1 ) via pulmonary insufflation. A laryngoscope was used to locate the rat's epiglottis and a blunt tip insufflator (Perm Century Insufflation powder delivery device, Pen Century, Inc., Philadelphia, PA, USA) was inserted into the airway. A bolus (3 X 3 ml) of air from an attached syringe was used to deliver the preloaded powder from the chamber of the insuffator into the rat's lungs. In oral group (Group T) the rats were dosed orally with Bupropion HCl, solubilized in 1% CMC solution. Blood samples (500μl) were drawn from each animal at specified time intervals and separated plasma was analyzed for Bupropion by HPLC.

Results of the experiment are tabulated in Table 2. Average ± SEM plasma concentration values in (ng/mL) obtained for the Group 1 and Group 2 of rats at various time points in minutes is given in the table below. Table 3: Plasma levels of Bupropion after pulmonary and oral administration (17mg/kg)

Targeted dose 17 mg/kg; and achieved average administered dose 16.27 mg/kg through insufflator device in pulmonary delivery

The data indicates that micronized bupropion HCl is very rapidly absorbed (5min) through pulmonary route and provides a remarkably high plasma concentration as compared to oral administration. Further in this invention, enhanced brain:plasma ratio is also expected through pulmonary administration over oral administration. Therefore, it is considered that pulmonary delivery of bupropion will demonstrate physiologically meaningful concentrations in brain and similar or enhanced pharmacodynamics over oral delivery at reduced dose.

Claims

Claims:

1. A pharmaceutical composition comprising particles of micronized bupropion having controlled particle size in the range between 1-60 μm wherein median particle size is less than 40 μm.

2. The pharmaceutical composition as claimed in claiml further comprises one or more pharmaceutically acceptable carriers, surfactant, dispersing agent or dispersant.

3. The pharmaceutical composition as claimed in claim 1 is in the form of dry powder composition.

4. The pharmaceutical composition as claimed in claim 3 wherein the dry powder composition is prepared by conventional milling, spray-drying, spray-freeze drying vacuum drying and precipitation method.

5. The pharmaceutical composition as claimed in claim 3 wherein the dry powder composition is suitable for oral, nasal, pulmonary, injectable or vaginal route of delivery.

6. The pharmaceutical composition as claimed in claim 5 wherein the dry powder composition is suitable for inhalation by nasal and pulmonary route.

7. The dry powder composition for inhalation as claimed in claim 6 comprising micronized bupropion and pharmaceutically acceptable carriers selected from group of proteins, peptides, amino acids, lipids, polymers, carbohydrates and combination thereof.

8. The dry powder composition for inhalation as claimed in claim 7 wherein the pharmaceutically acceptable carrier is carbohydrate selected from a group of fructose, glucose, lactose, sucrose, trehalose, dextrans mannitol, sorbitol, starch, pullulan, carrageenan, locust bean gum, xanthan gum, gellan gum, pectin and combination thereof.

9. The dry powder composition for inhalation as claimed in claim 8 comprising a blend of micronized bupropion and lactose wherein the lactose is present in the form of micronized lactose and coarse lactose or sieved fraction of lactose.

10. The dry powder composition for inhalation as claimed in claim 9 for nasal delivery comprising blend of micronized bupropion and lactose wherein the particle size of lactose is in the range of about 20 μm to about 350 μm.

11. The dry powder composition for inhalation as claimed in claim 6 comprising micronized bupropion and pullulan wherein bupropion is present in an amount ranging from about 0.1% w/w to about 50.0% w/w and pullulan is present in an amount ranging from about 1.0% w/w to about 30.0% w/w.

12. The dry powder composition for inhalation as claimed in claim 6 comprising micronized bupropion and surfactant selected from group of dipalmitoylphosphatidylcholine (DPPC), diphosphatidyl glycerol (DPPG); hexadecanol; , polyethylene glycol (PEG); polyoxyethylene-9- lauryl ether; palmitic acid, oleic acid; sorbitan trioleate, glycocholate;surfactin; a poloxomer; sorbitan trioleate; tyloxapol and combination thereof.

13. The dry powder composition for inhalation as claimed in claim 12 wherein the micronized bupropion is coated with dipalmitoylphosphatidylcholine wherein bupropion is present in an amount ranging from about 0.1% w/w to about 50.0% w/w and dipalmitoylphosphatidylcholine is present in an amount ranging from about 1.0% w/w to about 40.0% w/w.

14. The dry powder composition for inhalation as claimed in claim 6 comprising micronized bupropion for the prevention and treatment of diseases such as depression, premenstrual syndrome, premature ejaculation and as an aid to smoking cessation.

15. The process of preparing the dry powder composition as claimed in claim 6 comprising the steps of (a) forming the particles of micronized bupropion by conventional milling (b) dissolving the surfactant or the carbohydrate into a suitable solvent (c) adding micronized bupropion into the solution formed in step b (d) spray-drying the solution to obtain dry powder.