FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10]
"INHALANT COMPOSITIONS"
(a) CIPLALTD.
(b) 8, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956

The following specification describes the nature of the invention and the manner

in which it is to be performed:

Technical Field of invention:
The present invention relates to pharmaceutical composition comprising at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. More particularly relates to inhalant composition containing immunosuppressant for treatment of reversible obstructive respiratory disease, in particular asthma, and / or atopic dermatitis, and compositions suitable for such use.
Background and prior art:
The primary function of the immune system in the body is to defend the body from foreign substances. The immune system has two functional divisions of defense against foreign substances: specific and non-specific. The specific immune system recognizes and eliminates antigens with specialized cells, primarily macrophages and T and B-lymphocytes. T lymphocytes are primarily responsible for cell-mediated immunity, delayed hypersensitivity, transplant rejection and the like. B lymphocytes are responsible for humoral or antibody mediated immunity. There are four types of T lymphocytes: T-helper, T-suppressor, cytotoxic T cells and memory cells. T-helper cells regulate the cell-mediated response to antigens. When antigen is presented to the T-helper cells, they release interleukin-2 (IL-2) and Y-interferon, which in turn stimulate other helper T cells. Allograft rejection is both cell and antibody mediated, and it involves both helper and inducer T lymphocytes. These are sensitized by antigens released by donor allograft. This leads to injury or destruction of certain epithelial structures of the transplanted allograft. Immunosuppressants act on rejection prophylaxis and for the treatment of rejection.
Tacrolimus is a hydrophobic macrolide immunosuppressant produced by Streptomyces tsukubaensis No. 9993. It is reported as used in the treatment of rejection in transplantation and autoimmune diseases, and is routinely used in transplantation of for example, the kidney, liver or heart. Tacrolimus, 17-allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3 -methoxycyclohexyl)-1 -methylvinyl] -23,25-dimethoxy-13,19,21,27-
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tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04 9]octacos-18-ene-2,3,10,16-tetraone, which is also known as FK-506 or FR-900506, has the following structural formula:

Tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, cadmodulin and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. The effect has been shown to prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5,GM-CSF and TNF-alpha, all of which are involved in the early stages of T-cell activation. Tacrolimus inhibits proliferation and selective cytokine expression in antigen stimulated T cells in culture and also inhibits B cell proliferation at similar concentrations. Immunosuppression with tacrolimus in humans prevents allograft rejection.
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US Patent Application 2002052407, US Patent 6187756, US Patent 6184248 and WO 98/09523 describe compositions of tacrolimus for use in neurological disorders and neurogenerative diseases.
EP 1092429 discusses pharmaceutical compositions and methods for treating immune response associated disorders.
US Patent Applications 2002173516 and 2002013340 describe pharmaceutical compositions and methods for treating immune response associated diseases of the surface and anterior segment of the eye.
EP 1067926 and WO 99/51215 describe the use of tacrolimus as showing inhibitory activity on the production of nitric oxide.
Surprisingly it has now been found that tacrolimus may be used for treating diseases associated with asthma and related respiratory immune disorders. Atopic dermatitis has been identified for many years as a disease of immune deregulation, where the immune system in atopic dermatitis tends to over respond. The result of abnormal immune response and associated inflammation may be organ specific to the skin in atopic dermatitis. In asthma, also a disease where immune deregulation plays a role, inflammation is organ specific to the lung. In certain cases, asthma can precede the development of atopic dermatitis. In the affected organ (lung or skin respectively) the inflammation produces symptoms characteristic for the organ - constricted airways, wheezing and shortness of breath in the lung; itching and redness in the skin. Tacrolimus, and physiologically functional derivatives thereof, have now been found to be useful for treatment of the above, and in particular inhalant compositions comprising tacrolimus, or physiologically functional derivative thereof, have been found to be useful.
There are a number of advantages associated with the use of inhalers as a delivery system, such as convenience in use, multiple dose capacity, low dosage requirements for
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systemic absorption, little or no medication taste, available for relief and prophylactic use and usable by the majority of patients. By using this route of administration, usage of tacrolimus can be controlled in individual patients, with respect to asthma and related respiratory disorders, and also graft function (disease severity).
Summary of the invention:
Pharmaceutical composition containing at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, is disclosed. Further inhalant pharmaceutical composition containing immunosuppressant for treatment of reversible obstructive respiratory disease, in particular asthma, and / or atopic dermatitis, and compositions suitable are disclosed.
Detailed Description:
According to the present invention, therefore, there is provided at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, for use in the manufacture of a medicament for the treatment of reversible obstructive respiratory disease.
According to the present invention, therefore, there is also provided at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, for use in the manufacture of a medicament for the treatment of atopic dermatitis.
Preferably, the medicament comprises an inhalant medicament, typically in a form suitable for administration by way of a MDI, or DPI, substantially as hereinafter described in greater detail.
An immunosuppressant suitable for use according to the present invention is preferably selected from the group consisting of tacrolimus, cyclosporin, or a pharmaceutically
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acceptable salt, solvate or physiologically functional derivative thereof. Tacrolimus, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, is particularly preferred for use according to the present invention.
The present invention also provides a method for the treatment or prophylaxis of reversible obstructive respiratory disease, which method comprises administration to a patient suffering from, or susceptible to, reversible obstructive respiratory disease, a therapeutically effective amount of at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof substantially as hereinbefore described.
The present invention also provides a method for the treatment or prophylaxis of atopic dermatitis, which method comprises administration to a patient suffering from, or susceptible to, atopic dermatitis, a therapeutically effective amount of at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof substantially as hereinbefore described.
Preferably, according to a method of the present invention the immunosuppressant is administered to a patient in the form of an inhalant medicament, preferably in a form suitable for administration by way of a MDI, or DPI, substantially as hereinafter described in greater detail.
A method according to the present invention preferably comprises administration of an immunosuppressant selected from the group consisting of tacrolimus, cyclosporin, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Tacrolimus, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, is particularly preferred for use in a method according to the present invention.
The term "physiologically functional derivative" as used herein denotes a chemical derivative of an immunosuppressant as described herein having the same or similar
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physiological function as the free base immunosuppressant and, for example, being convertible in the body thereto.
The term "reversible obstructive respiratory disease" as used herein denotes inflammatory and obstructive airways disease, such as asthma, COPD and other related disorders. In particular, the present invention is directed to the use of at least one immunosuppressant for the treatment of asthma.
Medicaments suitable for use according to the present invention include those suitable for oral, parenteral, inhalation, rectal and topical administration, with inhalation being preferred, typically employing MDIs or DPIs. Such medicaments may conveniently be presented in unit dosage form and may be prepared by methods well known to one of ordinary skill in the art.
The present invention further provides, therefore, an inhalant composition comprising at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, suitable for use in the treatment of reversible obstructive respiratory disease, in particular asthma.
Preferably, an inhalant composition comprises an immunosuppressant selected from the group consisting of tacrolimus, cyclosporin, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Tacrolimus, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, is particularly preferred for use in an inhalant composition according to the present invention.
An inhalant composition according to the present invention can comprise a propellant-containing dosage aerosol, an inhalation powder or a propellant free inhalation solution or suspension. The compositions of the present invention may thus be provided by, for example, a metered dose inhaler (MDI), dry powder inhaler (DPI) or nebules.
In the case of a propellant-containing dosage aerosol, typically the propellant can be
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selected from the group consisting of 1,1,1,2-tetrafluoroethane (HFA 134a, or P134a as
referred to in the Examples), 1,1,1,2,3,3,3-heptafluoroethane (HFA 227), a combination
of 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoroethane,
monofluorotrichloromethane and dichlorodifluoromethane, and derivatives thereof, in particular 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoroethane (HFA 227). The use of 1,1,1,2-tetrafluoroethane (HFA 134a) is preferred.
In the case of a particulate suspension or a solution for the propellant-containing aerosol composition, the composition may further comprise one or more co-solvents. The composition may comprise both a propellant and a co-solvent, in which case it is desirable that the co-solvent has a greater polarity than the propellant. The co-solvent used may be any suitable solvent, and typical co-solvents for use in the present invention include C2-6 aliphatic alcohols and polyols, for example ethanol, isopropanol and propylene glycol. Preferably the co-solvent is ethanol. Generally the co-solvent is present in the range of 0.1 to 15% by weight of the total composition and the ratio of propellant to co-solvent is typically between 50:50 to 99:1.
If aerosolized, the composition may further comprise a surface-active agent to stabilize the composition and for the lubrication of a valve system in the inhaler/nebuliser/nasal spray.
Some of the most commonly used surface-active agents in aerosol compositions are oils derived from natural sources, such as corn oil, olive oil, cotton seed oil and sunflower seed oil and also phospholipids. Preferred surfactants for use according to the present invention are oleic acid, lecithin or polyethylene glycol. In these embodiments, the surface-active agents are preferably used in the compositions in the ratio of 0.0001 wt% wt to 20 wt% of the immunosuppressant active ingredients. The surface-active agents may exceed this weight ratio in cases where immunosuppressant concentration in the composition is very low.
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The immunosuppressant active ingredients in all the above aerosol compositions are preferably in the concentration of 0.001 wt% to 5 wt% of the total composition.
The immunosuppressant active ingredients are preferably provided in an appropriate particle size, generally in the range from nano-size to about 12 urn. Preferably, approximately 95% are below 5 or 6 um (micrometers), with the all particles being below 12 um (when measured by laser), or approximately 95% below 2.5 um and the rest of the particles between 2.5-5 urn (when measured by microscope).
According to another aspect of the invention there is provided an aerosol device, comprising a housing containing a composition as described above, and a dispensing mechanism for dispensing the composition from the housing in a metered dose.
The dispensing mechanism may include a valve capable of releasing a metered dosage of the composition. Preferably the housing is sealed and pressurized at a pressure exceeding atmospheric pressure.
The housing may be metallic, preferably aluminum. Preferably, the housing is plastic-coated, lacquer-coated or anodised. The composition of the present invention may be placed in the housing through a suitable metering device.
In the case where an inhalant composition according to the present invention is provided as inhalation powders, typically suitable pharmaceutically acceptable excipients may be selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides or the like, with the use of lactose as the excipient in the inhalation powders of the present invention being preferred. The inhalation powders of the present invention can typically be administered by means of dry powder inhalers known in the art.
Alternatively, an inhalant composition according to the present invention can be provided as an inhalation solution typically suitable for administration by way of nebulisation, employing nebulisers well known in the art that can advantageously be employed to
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produce inhalable aerosols comprising the immunosuppressant active ingredients according to the present invention.
There is further provided by the present invention a process of preparing an inhalant composition substantially as hereinbefore described, which process comprises providing at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, in the form of a composition suitable for administration by inhalation by way of a metered dose inhaler (MDI), dry powder inhaler (DPI), or a nebuliser.
The present invention will now be further illustrated by the following Examples, which do not limit the scope of the invention in any way.
Examples
Example 1

Ingredients Qty/can
Tacrolimus 6mg to 96mg
P134a\ 18.2gms
In the above composition tacrolimus was first weighed in an aluminum can. The metering valve was placed on the can and crimped with a vacuum crimper, and then propellant P 134a was charged through the metering valve.
Example 2

Ingredients Qty/can
Tacrolimus 6mg to 96mg
Ethanol 0.1 to 15% (based on composition)
P134a 18.2gms
In the above composition tacrolimus was first weighed in an aluminum can, then the ethanol was added and the solution was sonicated for 5 min. The metering valve was placed on the can and crimped with a vacuum crimper, and then propellant P 134a was
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charged through the metering valve. Example 3

Ingredients Qty/can
Tacrolimus, 6mg to 96mg
Ethanol 0.1 to 15% (based on composition)
Oleic acid 0.001% to 20% (of tacrolimus)
P134a 18.2gms
In the above composition tacrolimus was first weighed in an aluminum can, then the ethanol and oleic acid were added and the solution was sonicated for 5 min. The metering valve was placed on the can and crimped with a vacuum crimper, and then propellant P 134a was charged through the metering valve.
Example 4

Ingredients Qty/can
Tacrolimus 6mg to 96mg
Ethanol 0.1 to 15% (based on composition)
Lecithin 0.001% to 20% (of tacrolimus)
PI 34a 18.2gms
In the above composition tacrolimus was first weighed in an aluminum can, then th