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A Low Dose Corticosteroid Composition

Abstract: N/A

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Patent Information

Application #
Filing Date
17 February 2003
Publication Number
0
Publication Type
INA
Invention Field
GENERAL ENGINEERING
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2007-07-25
Renewal Date

Applicants

SUN PHARMACEUTICAL INDUSTRIES LTD.
ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (EAST), MUMBAI - 400 059.

Inventors

1. DR. SUBHAS BALARAM BHOWMICK
SUN PHARMA ADVANCED RESEARCH CENTRE., AKOTA ROAD, AKOTA, BARODA 390 020. GUJARAT

Specification

The present invention relates to a low dose corticosteroid composition of budesonide said composition being suitable for administration of budesonide to mucosal membranes. Particularly the present invention relates to a low dose composition of budesonide suitable for administration of budesonide to mucosal membranes for the management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis comprising budesonide at a therapeutically effective dose of less than 16 meg and a pharmaceutically acceptable liquid carrier. The preferred low dose composition of budesonide suitable for administration of budesonide to the mucosal membranes is a stable aqueous solution composition of budesonide. BACKGROUND OF THE INVENTION Budesonide, a synthetic corticosteroid, is an antiinflammatory agent useful for prophylaxis and treatment of asthma, and for treatment of perennial and seasonal allergic rhinitis. It is available in the form of an oral inhalation powder (PULMICORT® TURBUHALER, 200mcg), and oral inhalation suspension (PULMICORT®RESPULES, 0.25mg & 0.5mg) for maintenance treatment of asthma and as prophylactic therapy. For rhinitis, it is available as a metered-dose nasal spray formulation (RHINICORT AQUA. 32mcg) containing budesonide in aqueous suspension and a metered-dose pressurized aerosol unit (RHINOCORT Nasal Inhaler) containing a suspension of micronized budesonide in a mixture of propellants, (dichlorodifluromerhane, trichloromonofluromethane and dichlorotetrafluoroethane) and sorbitan trioleate. Rhinocort nasal inhaler is a metered-dose pressurized aerosol unit, wherein each actuation releases 50 meg budesonide from the valve and delivers approximately 32 meg budesonide from the nasal adapter. The recommended starting dose is 256 meg daily, given as either two sprays in each nostril morning and evening and as four sprays in each nostril in the morning. Rhinocort aqua, nasal spray 32 meg. is a metered-dose, manual pump spray formulation, whose recommended starting dose for adults and children 6 years of age and older is 64 meg per day administered as one spray per nostril once daily. The maximum recommended dose for adults is 256 meg per day and for pediatrics is 128 meg per day. The Rhinocort aqua, nasal spray 32 meg, is a metered-dose, manual-pump spray formulation containing a micronized suspension of budesonide in an aqueous medium. Systemic corticosteroid effects such as hypercorticism and adrenal suppression, has been reported to occur with the administration of larger doses of corticosteroids and hence it is recommended to use minimal effective dose of budesonide nasal spray. As mentioned above, for Rhinocort aqua, the recommended starting dose is 64 meg per day administered as one spray per nostril of the available 32 meg Nasal spray once daily which may be increased if the patients do not achieve the symptom control but in order to reduce the possibility of side effects it is always desirable to titrate an individual patient to the minimum effective dose. We have now surprisingly found that a lower metered spray dose of budesonide than that previously recommended is effective for the management of nasal symptoms associated with allergic rhinitis and is also well tolerated when administered intranasaly. Thus we provide a composition comprising budesonide at a therapeutically effective dose of less than 16 meg and pharmaceutically acceptable liquid carrier such that the composition is suitable for administration of budesonide to the mucosal membranes for the management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis. United States Application No. US20020016315A1 discloses a metered unit dose comprising 40 meg or less of budesonide, its formulations and its use for the treatment of conditions in the nose. The patent exemplifies a suspension comprising 32 meg budesonide. Studies on the marketed preparation Rhinocort® Nasal spray shows that a 32 meg suspension is efficacious. There is no study or publication demonstrating that doses less than 16 meg may be also efficacious. We have found novel compositions comprising budesonide at a therapeutically effective dose of less than 16 meg that are effective in management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis thus meeting the much needed requirement of providing a less dose of a corticosteroid for therapeutic efficacy to reduce the possibility of side effects. Thus a low dose composition of budesonide wherein the composition is suitable for administration of budesonide to mucosal membranes for the management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis wherein the composition comprises of budesonide at a therapeutically effective dose of less than 16 meg and pharmaceutically acceptable liquid carrier is provided in the present invention. Further we have also found an aqueous pharmaceutically acceptable liquid carrier for budesonide wherein budesonide is present in dissolved form and when stored at room temperature for one year there is no precipitation of budesonide over the one-year period. More particularly we also found stable aqueous solution composition of budesonide which are free of alocoholic cosolvents suitable for administration of budesonide to mucosal membranes for the management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis such that the composition is efficacious and well tolerated when administered at a metered spray dose of less than 16 meg per nostril. Further we have also found an aqueous pharmaceutically acceptable liquid carrier for budesonide wherein budesonide is present in dissolved form and when stored at room temperature for one year there is no precipitation of budesonide over the one-year period. More particularly we also found stable aqueous solution composition of budesonide which are free of alocoholic cosolvents suitable for administration of budesonide to mucosal membranes for the management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis such that the composition is efficacious and well tolerated when administered at a metered spray dose of less than 16 meg per nostril. Budesonide, because of its high lipophilicity, is virtually insoluble in water. Hence, there are considerable difficulties in formulating aqueous solutions of budesonide including the need for the addition of solvents like alcohols, to keep the drug in solution. It is however desirable to avoid the use of alcoholic cosolvents. For example in a study reported in Ann Allergy 1988, Oct;(4):305-310, wherein the study compared the incidence of nasal burning and stinging, as well as overall tolerability of the currently marketed formulation of Rhinalar (flunisohde, marketed formulation) to a new formulation of Rhinlar containing less propylene glycol, the results showed a very significant difference in terms of severity, duration and tolerability in favour of the new formulation. Moreover the effects of long-term use of preparations containing substantial amount of a cosolvent are not known. Also, United States Patent No. 6,241,969 has stated that there are limits to acceptable levels of cosolvents included in inhaled products and the limits are set by the propensity of these solvents either to cause local irritation of lung tissue and/or to intoxicate the patient. However, the problem associated with aqueous solutions of budesonide free of alcoholic cosolvent is that the drug undergoes decomposition, and because of its low solubility in water, it has a tendency to precipitate on storage at room temperature. It is thus a further object of the present invention to provide stable aqueous solution composition of budesonide characterized in that the composition is free from an alcoholic solvent and when stored at room temperature for one year exhibits no precipitation of budesonide. The said aqueous composition comprises budesonide and a complexing agent and has a pH not exceeding 6.0. Various techniques used in prior art to develop stable budesonide solutions are given below. Patentees in United States Patent No. 5,914,122 disclosed that although prior to their invention budesonide aqueous solutions could be prepared with the help of organic water-soluble alcohols, in these solutions budesonide decomposed within a short time and thus prior to the invention ready to use stable solution preparations of budesonide were not known. The patent claims stable budesonide solution with pH less than 6.0 wherein budesonide is dissolved in a solvent selected from the group consisting of water, alcohol, and a water/alcohol mixture and wherein the alcohol is selected from ethanol, isopropanol and propylene glycol. Alcohol free aqueous solution compositions of budesonide that were stable with respect to chemical decomposition of budesonide as well as free from precipitation of budesonide upon storage at room temperature were not disclosed. The patent further claims that the composition further comprises stabilizing additives selected from sodium EDTA (0.001%-0.1% w/w) and cyclodextrin (0.05%-1.0% by weight). United States Patent No. 6,241,969 claims aerosolized composition of a corticosteroid to respiratory tract consisting essentially of 5 mcg/ml to 5 mg/ml of the corticosteroid, about 0.1 to about 20% by weight of a high-HLB surfactant component comprising atleast 50% by weight of an ethoxylated derivative of vitamin E and at least about 70% by weight of an aqueous phase. All the supportive examples of the composition, however, illustrate compositions that comprise both a high-HLB surfactant as well as a cosolvent like propylene glycol, ethanol, polyethylene glycol etc. Budesonide is one of the corticosteroids further claimed in this patent. The high-HLB surfactant component exemplified and claimed is tocopheryl polyethylene glycol 1000 succinate. The invention further discloses addition of excipients such as buffers, osmotic agents, low toxicity antifoarning agents and preservatives. When buffers are used for pH adjustment, the recommended range is of pH within 4-8 and more preferably within 5-6.8. The patented composition does not contain any complexing agent that complexes budesonide. United States Application No. US20020031558A1 claims clear aqueous solutions of bile acids, bile acid derivatives, bile salts or conjugated bile acids, which remain in solution over range of pH values. These aqueous compositions were useful whea orally,administered for treating gastric and peptic ulcer disease, liver disease, gall stones and hyperlipidemia. The invention thus relates to the therapeutic potential of bile acid, salts, derivatives or conjugates. However it claims in dependent claims also clear solutions as defined above further comprising pharmaceutically effective compounds. The only example supporting this further claim uses bismuth citrate as the pharmaceutically effective compound. According to the claims, the clear aqueous solution may also be administered intranasally. Although budesonide is one of the pharmaceutically effective compounds the patent does not exemplify such compositions and therefore does not address issues such as chemical stabilization of budesonide, or prevention of precipitation of budesonide over a period of time of storage. The disclosed compositions do not contain a complexing agent capable of complexing with budesonide. PCT Application WO 01/07014 claims a stable formulation for inhalation through nebulization consisting of a solution of a steroid in which (a) the steroid concentrations ranges from 0.01%-0.1%; (b) the carrier is a mixture of water and propylene glycol in a ratio ranging from 60:40 to 30:70 v/v; and (c) pH is adjusted with concentrated strong acid in a range from 3.5 to 5.0; wherein the percentage of nebulized active ingredient particles with mean aerodynamic diameter below 6um is higher than 70% and the nebulization efficiency is higher than 20%. Budesonide or its epimers are further claimed as one of the steroids. The inventors found that the solutions adjusted to pH 4 and 4.5 remained stable. The inventors further studied stability of the budesonide solutions by adjusting the pH using buffers consisting of different relative percentages of sodium phosphate and citric acid buffers. They concluded that inclusion of buffers resulted in less stable solutions. A high concentration of an alcoholic solvent like propylene glycol used in the disclosed formulation is undesirable for use on mucosal membranes. Russian Patent No. RU2180217 discloses a stable budesonide solution with an anti-inflammatory effect that contains budesonide, propylene glycol, polyethylene oxide, benzoic acid, Trilon B, nipazole, thiourea and water. The solution can additionally contain 2-hydroxypropyl-beta-cyclodextrin. PCT Publication No. WO 01/87203 claims a stable budesonide solution comprising budesonide and a solvent wherein after about 12 weeks, budesonide is present in solution in an amount at least about 90% preferably at least about 95%, most preferably at least about 99% of the initial budesonide concentration in the solution. The solvent used was generally a non-aqueous solvent such as polyhydric alcohol or glycol, more preferably propylene glycol or triethylene glycol but water could be added as a cosolvent. United States Patent No. 6,491,897 claims a stable pharmaceutical budesonide aerosol solution with a pH between 2.0 and 7.0 in which the budfesdnide Is dissolved in a water/ethanol mixture, which mixture optionally includes an alcohol selected from the group consisting of isopropanol and propylene glycol and wherein the stable solution comprises 0.001% to 5% by weight of budesonide. All the disadvantages quoted above with regard to use of alcoholic cosolvents in nasal and pulmonary delivery systems will apply to this patented composition. United States Patent No. 4,383,992 claims a water-soluble inclusion compound formed by complexing beta-cyclodextrin with a steroid compound having a molecular structure smaller than the inside dimension of file 'internal cavity of beta-cyclodextfm- Another mdepenierft c'la'irn diairns, an arm-inflammatory pharmaceutical preparation comprising the above inclusion compound mixed with non-toxic pharmaceutical carrier. The example in this patent, teaches the method of forming the inclusion compound of beta-cyclodextrin and the steroids (like, prednisolone acetate or dexamethasone or hydrocortisone) wherein dispersing ag^nt like hydroxypropyl methylcellulose has also been added and a solution obtained. The patent however does not disclose inclusion complex formation of budesonide with beta-cyclodextrin and whether it would provide a stable formulation. Nor does it address issues such as the pH requirement for stabilization of budesonide solutions or the prevention of precipitation of budesonide over a period of time of storage. OBJECTS OF THE INVENTION The objects of the invention are - 1) To provide a low dose corticosteroid composition of budesonide suitable for administration of budesonide to mucosal membranes. 2) To provide a low dose composition of budesonide suitable for intranasal administration of budesonide for the management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis wherein the composition comprises of budesonide at a therapeutically effective dose of less than 16 meg per nostril. 3) To provide a composition as in 2 above wherein the composition comprises budesonide and pharmaceutically acceptable liquid carrier wherein the liquid carrier is aqueous. 4) To provide an aqueous solution composition of budesonide which is free of alcoholic solvents. 5) To provide an aqueous solution composition of budesonide which is substantially free of a cosolvent. 6) To provide aforesaid aqueous solution composition of budesonide wherein budesonide is stabilized against its chemical decomposition. 7) To provide aforesaid aqueous solution composition where instead of solubilising budesonide with alcoholic cosolvents, the solubilization is achieved by the use of a complexing agent capable of forming a complex with budesonide. 8) To also provide aforesaid aqueous solution composition as in 7 above wherein further the propensity of budesonide to precipitate on long-term storage is inhibited. 9) To provide aqueous solution composition of budesonide having a low local irritation of mucosal membranes. 10) To provide aqueous solution composition of budesonide having a high availability of budesonide at the site of action. 11) To provide an aqueous solution composition of budesonide having a high availability at the site of action and reduced systemic availability of budesonide or its metabolites. 12) To provide an aqueous solution composition of budesonide as in 11 above and having a low dose of budesonide. 13) To provide a method of treatment for management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis by administering budesonide intranasaly at a therapeutically effective dose of less than 16 meg per nostril. 14) To provide a method of treatment for management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis by administration of a stable aqueous solution comprising budesonide in a dissolved form. SUMMARY OF THE INVENTION Thus the present invention provides a low dose composition of budesonide suitable for administration of budesonide to mucosal membranes. The present invention particularly provides a low dose composition of budesonide suitable for administration of budesonide to mucosal membranes for the management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis wherein the composition comprises of budesonide at a therapeutically effective dose of less than 16 meg and a pharmaceutically acceptable liquid carrier. The present invention more particularly provides a low dose composition of budesonide wherein the composition is a stable aqueous solution composition of budesonide said composition being suitable for administration of budesonide to mucosal membranes for the management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis such that the composition is efficacious and well tolerated when administered at metered spray dose of less than 16 meg per nostril. The said composition comprises budesonide and pharmaceutically acceptable liquid carrier wherein the liquid carrier is aqueous and budesomde is present in dissolved form and when stored at room temperature for one year there is no precipitation of budesonide over the one-year period. Particularly the said composition is a stable aqueous solution composition comprising budesonide in an aqueous medium, which is free from an alcoholic cosolvent wherein the medium comprises a complexing agent wherein, said aqueous solution has a pH not exceeding 6.0 Thus a method of treatment for the management of nasal symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis and recurrent sinusitis in a mammal in need thereof which comprises intranasal administration of budesonide at a therapeutically effective dose of less than 16 meg per nostril is provided herewith in the present invention. DETAILED DESCRIPTION OF THE PRESENT INVENTION According to the invention we provide a low dose composition comprising budesonide and pharmaceutically acceptable liquid carrier. We particularly provide an aqueous solution composition of budesonide which is effective when administered at a metered spray dose of less than 16 meg per nostril said composition being suitable for nasal administration to a mammal in a single dose for the treatment of nasal symptoms associated with seasonal allergic rhinitis, perennMnflle rhin{tis,

Documents

Application Documents

# Name Date
1 197-mum-2003-form 1(17-02-2003).pdf 2003-02-17
1 abstract1.jpg 2018-08-08
2 197-mum-2003-form 5(16-02-2004).pdf 2004-02-16
2 197-mum-2003-correspondence(ipo)-(08-03-2007).pdf 2007-03-08
3 197-mum-2003-form 3(16-02-2004).pdf 2004-02-16
3 197-mum-2003-cancelled pages(12-02-2007)0060.pdf 2007-02-12
4 197-mum-2003-form 18(05-10-2005).pdf 2005-10-05
5 197-mum-2003-form-pct-isa-210(12-02-2007).pdf 2007-02-12
5 197-mum-2003-claims(granted)-(12-02-2007).pdf 2007-02-12
6 197-mum-2003-form-pct-ipea-409(12-02-2007).pdf 2007-02-12
6 197-mum-2003-correspondence(12-02-2007).pdf 2007-02-12
7 197-mum-2003-form 2(granted)-(12-02-2007).pdf 2007-02-12
7 197-mum-2003-drawing(12-02-2007).pdf 2007-02-12
9 197-mum-2003-form 2(granted)-(12-02-2007).pdf 2007-02-12
9 197-mum-2003-drawing(12-02-2007).pdf 2007-02-12
10 197-mum-2003-correspondence(12-02-2007).pdf 2007-02-12
10 197-mum-2003-form-pct-ipea-409(12-02-2007).pdf 2007-02-12
11 197-mum-2003-form-pct-isa-210(12-02-2007).pdf 2007-02-12
11 197-mum-2003-claims(granted)-(12-02-2007).pdf 2007-02-12
12 197-mum-2003-form 18(05-10-2005).pdf 2005-10-05
13 197-mum-2003-form 3(16-02-2004).pdf 2004-02-16
13 197-mum-2003-cancelled pages(12-02-2007)0060.pdf 2007-02-12
14 197-mum-2003-form 5(16-02-2004).pdf 2004-02-16
14 197-mum-2003-correspondence(ipo)-(08-03-2007).pdf 2007-03-08
15 abstract1.jpg 2018-08-08
15 197-mum-2003-form 1(17-02-2003).pdf 2003-02-17

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