Field of the Invention:
The present invention relates to a pharmaceutical composition of N-(3,5- dichloropyridin-4-yl)-3 -cyclopropylmethoxy-4-difluoromethoxy-benzamide and its preparation thereof. Further, the said pharmaceutical composition is useful for the treatment of chronic obstructive pulmonary disease (COPD).
Background of the Invention:
N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy- benzamide with an empirical formula C17H14CI2F2N2O3 and the molecular weight is 403.22. Structure of the N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoro methoxy-benzamide is as follows:
N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy- benzamide is a drug which acts as a selective, long-acting inhibitor of the enzyme PDE - 4. It has anti-inflammatory effects and orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, and chronic obstructive pulmonary disease (COPD).
Cyclic nucleotide phosphodiesterase (PDE) inhibitors (specifically of type 4) are currently of special interest as a new generation of active ingredients for treating inflammatory disorders, especially inflammations of the airways such as asthma or airway obstructions (for example COPD: chronic obstructive pulmonary disease).
N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy- benzamide is commercially available as a tablet for oral administration (Daliresp®, marketed by Forest Res. in US and Daxas® is marketed by Nycomed, Europe).
N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe
COPD associated with chronic bronchitis and a history of exacerbations.
US Patent No. 5712298 describes a fluoroalkoxy-substituted benzamide, known as N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, which is used as cyclic nucleotide phosphodiesterase inhibitors.
US Patent No. 7951397 discloses the pharmaceutical composition comprising of N- (3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide and polyvinyl pyrrolidone (PVP) as a binder provides a dosage form with improved bioavailability.
US Patent No. 8536206 discloses method of treating COPD by administering a pharmaceutical tablet comprising 0.5mg of N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide having a purity of greater than or equal to 99% by weight; N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-hydroxybenzamide present in an amount less than 0.1% by weight.
The solubility of PDE-4 inhibitor class is very low in water and aqueous systems which may be depending on the chemical structure of the active ingredient. Thus, the solubility in water found for the PDE-4 inhibitor N-(3,5 dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, which is described in US5712298, is only 0.53 mg/1 at 21°C. The bioavailability of a medicinal substance depends essentially on the release of the medicinal substance from the pharmaceutical form. Faster release and dissolution of the medicinal substance from the formulation means faster absorption thereof. Medicinal substances, which are slightly soluble in water, may have lower dissolution. Therefore, the bioavailability is frequently limited by the solubility or rate of dissolution. This makes it very difficult to produce suitable dosage forms.
Without being bound by any theory, the inventors of the present invention surprisingly been found that the solid pharmaceutical composition according to the invention exhibits a dissolution profile and bioavailability that is atleast comparable to that of known Daliresp formulations, particularly formulations comprising N-(3,5-dichloropyridin-4-yl)-3- cyclopropylmethoxy-4-difluoromethoxy-benzamide without PVP as a binder, while allowing for substantially less complex and inexpensive preparation.
The present invention provides the pharmaceutical composition for N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide in the form of oral dosage form having the following advantages:
> Enriched release profile is observed with pregelatinized starch (starch 1500) and surfactant and /or solubilizers.
> Usage of pregelatinized starch (starch 1500) and surfactant and /or solubilizers enhanced the stability of the formulation when compared to the other excipients such as hydroxypropylmethylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone.
> Superior physical properties were observed with pregelatinized starch (starch 1500) and surfactant and /or solubilizers when compared with other excipients.
Another advantage is that the solid pharmaceutical composition according to, the invention can be prepared in the absence of organic solvent, which results in a lower consumption of energy and which is more environment friendly.
The inventors of the present invention have developed a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difiuoromethoxy-benzamide as active ingredient and which provides better or comparative, content uniformity, control of related substances, dissolution profile and/or bioavailability w.r.t commercialized dosage forms.
Henceforth, it is an object of the present invention to provide a stable pharmaceutical composition comprising N-(3,5dichloropyrid-4-yl)-3-cyclopropylmethoxy-4- difluoromethoxy-benzamide avoiding these drawbacks and which is not only bioequivalent with the known formulations of Daliresp®, but which can also be prepared from inexpensive excipients and can be prepared using a simple and economical process that is suitable for industrial application.
Summary of the Invention:
The present invention relates to a pharmaceutical composition of N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide for the treatment of chronic obstructive pulmonary disease (COPD).
One embodiment of the present invention is to provide the pharmaceutical composition comprising N-(3,5-dichloro pyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, surfactant and /or solubilizers.
Another embodiment, the pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, pregelatinized starch, surfactant and/or solubilizers, and optionally a pharmaceutically acceptable excipient:
In a prefered embodiment, the stable pharmaceutical composition comprising N-(3,5- dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, lactose monohydrate, pregelatinized starch, polysorbate and magnesium stearate.
In an another embodiment, the pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, characterized in that at least 90% by volume of the N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide particles are having less than about 20um, pregelatinized starch, surfactant and /or solubilizers, and optionally a pharmaceutically acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprising N-(3,5- dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difiuoromethoxy-benzamide is prepared by wet granulation technique. In a preferred embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy- benzamide is prepared by wet granulation technique; preferably with aqueous granulation.
In another embodiment of the present invention relates to an improved process for the solid oral dosage pharmaceutical composition which comprising of the following steps:
d) weighing quantities of N-(3,5-dichloropyridin-4-yl)-3-cyclopropyl methoxy-4- difiuoromethoxy-benzamide, a suitable diluent and passing through a appropriate mesh,
e) mixing the N-(3j5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoro methoxy-benzamide, a suitable diluent for appropriate period.
f) granulating the above blend with aqueous solution of surfactant and /or solubilizers,
g) drying the granules,
h) lubricating the above dried granules with lubricants,
i) compressing into tablets,
j) optionally coating the core tablet.
In a prefered embodiment of the present invention relates to an improved process for the solid oral dosage pharmaceutical composition which comprises the following steps:
a) weighing quantities of 0.1-1.0 wt% of N-(3,5-dichloropyridin-4-yl)-3-cyclopropyl methoxy-4-difluoromethoxy-benzamide, 5.0-80 wt% lactose monohydrate, 5.0-50 wt% pregelatinized starch (starchl500) and passing through a appropriate mesh,
b) mixing of N-(3,5-dichloropyridin-4-yl)-3-cyclopropyl methoxy-4-difluoromethoxy-benzamide, lactose monohydrate and pregelatinized starch (starchl500),
c) granulating the above blend with aqueous solution of less than 1.0 wt% surfactant and /or solubilizers,
d) drying the granules,
e) lubricating the above dried granules with 1-5 wt% of magnesium stearate,
f) compressing into tablets,
g) optionally coating the core tablet.
In another embodiment, the composition according to the invention exhibits a release profile characterized in that at least 40%, particularly at least 50%, more preferably at least 60%, most preferably at least 70% by weight of the active agent are released within a period of 10 minutes in 1000 ml of 1% sodium dodecyl sulfate in pH 6.8 Phosphate buffer, lOOOmL, Paddle, 50 RPM.
In another embodiment, the pharmaceutical composition comprising N-(3,5- dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is in the form of tablet, capsule, pellet, mini-tablet, granules and powder.
An another embodiment, the pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3 -cyclopropylmethoxy-4-difluoromethoxy-benzamide for oral administration for the treatment of chronic obstructive pulmonary disease (COPD).
Detailed Description of the Invention:
The present invention relates to a pharmaceutical composition of N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, and the process for its preparation thereof. Further, the said pharmaceutical composition is useful for the treatment of chronic obstructive pulmonary disease (COPD).
The term "pharmaceutical composition" (synonymously, "formulation") is used herein to refer to a pharmaceutical preparation intended for oral administration, includes such dosage forms as tablets, capsules, mini tablets, pellets, granules and spheroids. Preferably, solid oral dosage form is in the form of a tablet or a capsule.
By "salt'* or "pharmaceutically acceptable salt", it is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use. Representative acid additions salts include the hydrochloride, furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
The term "treating" or "treatment" as used herein also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide in a mammal.
The term "subject" includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). Preferably, the subject is a human.
By "pharmaceutically acceptable excipients" or "excipient", it is meant for any of the components of a pharmaceutical composition other than the active substance and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
The process according to the invention preferably comprises single-stage or multistage micronization of N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4- difiuoromethoxy-benzamide to obtain N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4- difluoromethoxy-benzamide in micronized form with d9o < about 40 um, preferably d9o