Indian Patents. 258190:"ADIRECT-ACTING OR NITRIC OXIDE DONOR BASED RESPIRATORY FORMULATION FOR MANAGEMENT OF PULMONARY HYPERTENSION & OTHER HYPOXIC AND A PROCESS FOR THE PREPARATION THEREOF"

Title of Invention	"ADIRECT-ACTING OR NITRIC OXIDE DONOR BASED RESPIRATORY FORMULATION FOR MANAGEMENT OF PULMONARY HYPERTENSION & OTHER HYPOXIC AND A PROCESS FOR THE PREPARATION THEREOF"
Abstract	A composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia which comprises from 0.1% - 3.6% wt of an active ingredient selected from nitric oxide donor and direct acting smooth muscle relaxants, from 4.3-44.4% of alkyl or aryl alcohol, from 60-99.99% of a suitable vehicle and the balance if any, comprising of conventional carriers and adjuvants.

Full Text	FILED OF THE INVENTION The present invention relates to a composition for use in the immediate or quick reduction of pulmonary hypertension. More, particularly, the present invention relates to a composition for use in the immediate or quick reduction of pulmonary hypertension and increases blood oxygen. In particular, the present invention relates to a nitric oxide donor based respiratory composition for management of pulmonary hypertension and other hypoxic hypoxema. The present invention also relates to a process for the preparation of nitric oxide donor based respiratory composition and the use thereof in the treatment and management of pulmonary hypertension and other hypoxic hypoxema.. PRIOR ART Pulmonary hypertension generally relates to pulmonary vasoconstriction, usually diffuse in pulmonary microcirculation leading to increase in pulmonary vascular resistance and pulmonary artery pressure. Pulmonary hypertension can be primary (cause unknown) or secondary to a number of lung diseases. Primary pulmonary hypertension has no successful treatment and leads to mortality in the long run. Secondary pulmonary hypertension almost always complicates a number of respiratory diseases like chronic obstructive airway disease and its variants, bronchial asthma, diffuse tuberculosis, emphysema, interstitial lung disease and Adult Respiratory Distress Syndrome. Still further, it is associated with high altitude, acute and chronic mountain sickness and high altitude pulmonary edema. Pulmonary hypertension, particularly with hypoxemia may become so severe as to cause death or severe incapacitation.. A further complication is pulmonary edema, pulmonary hemorrhages and hemoptysis. Still another complication of pulmonary hypertension is right-sided heart enlargement and failure. The medical management methods known in the art are inadequate to meet the challenge of this common and frequently a fatal problem. The treatments are either slow, relatively ineffective, expensive, cumbersome, or a combination thereof. One of the main treatment modalities is systemically delivered vasodilators that attempt to dilate the pulmonary blood vessels by administration of the drug orally or by injection. Drugs like prazocin, nifedipine, phentolamine and sildenafil have been used for the purpose. The main problem with systemic delivery is that a high dosage in the circulation is required for the desired effect because the drug is distributed throughout the body fluids. The very usage causes side effects like hypertension, significant palpitation and limits the use of this treatment. The known treatments also limit the duration of treatment to a few days or weeks only while most of the diseases with which pulmonary hypertension is associated are chronic in nature and may require treatment for years or even for life. Furthermore, systemic vasodilator therapy becomes reversed for very severe cases only while most patients have mild to moderate problem. Also, the effect is slow and delayed and not suited for conditions where fast action is desired. Systemic vasodilators are therefore, now considered an inadequate treatment in pulmonary hypertension but continue to be given in absence of a better treatment choice. For fast management of pulmonary hypertension, particularly with hypoxemia, oxygen inhalation is prescribed. However, the therapy does not treat pulmonary hypertension; it only reduces its effect. Also, it can only be given only for short periods. Furthermore, it is expensive and mostly requires infrastructural facilities for administration. It immobilized the patient for the period of therapy. Thus, it is useful only as an adjunct treatment for a short period. Yet another line of treatment is Nitric Oxide inhalation therapy. However, the therapy can only be given in severe cases and is not suitable for prolonged or continuous use. Secondly, it is expensive, and not indegenously available even in most of the super-specialty hospitals in India. It is essentially a hospital-based treatment and can be hazardous. Further, it confines the patient for the period of therapy. Thus, it is useful only for short-duration treatment and cannot be used routinely. OBJECTS OF THE INVENTION Thus, considering the widespread nature of the disease (primary or secondary pulmonary hypertension), its fatal or incapacitating nature, and further considering the inadequacy of the present line of management with respect to control or cure, side effects, cost-effectiveness, patient comfort or availability, there is an urgent need for a new treatment methodology for fast and effective treatment of this serious condition. Accordingly, it is an important object of the present invention to provide a composition for use in the immediate or quick reduction of pulmonary hypertension. It is another object of the present invention to provide a composition for use in the immediate or quick reduction of pulmonary hypertension and increases blood oxygen. It is yet another object of the present invention to provide a nitric oxide donor based respiratory composition for management of pulmonary hypertension and other hypoxic hypoxema. It is yet another object of the present invention to provide a process for the preparation of nitric oxide donor based respiratory composition and the use thereof in the treatment and management of pulmonary hypertension and other hypoxic hypoxema. It is yet another object of the present invention to provide a novel composition and process of its preparation that can be used as a fast method for management of primary pulmonary hypertension, secondary pulmonary hypertension and hypoxic hypoxemic states, but without implying any limitation of its use. It is yet another object of the present invention to provide a composition that increases the pulmonary blood circulation and oxygen transfer to blood by either acting directly on the smooth muscles of pulmonary microvasculature or by producing nitric oxide locally that in turn causes smooth muscle relaxation of pulmonary microvasculature. It is yet another object of the present invention to provide a composition that help in reduce the size of the aerosized drug particles prior to inhalation and make it possible for the various embodiments of the composition to be given through various types of inhalation devices to produce dry or wet inhalable aerosolized drug particle of very small dimensions. SUMMARY OF THE INVENTION In view of the severe limitations of the current treatment methods as exposed above, the present inventors have given great emphasis in developing a new strategy for treating or preventing pulmonary hypertension that may be very effective in quick control of disease and its symptoms and complications. It is also cost-effective, non-hazardous, capable of being used with minimal infrastructure needs, and easy to perform at field level. The concept used by the present invention that of inhalation therapy for alveolar deposition (ITAD) through nebulization, is a novel concept and the formulation that has been developed based on the concepts is a novel formulation. Accordingly, the present invention provides a composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia which comprises from 0.1% - 3.6% wt of an active ingredient selected from nitric oxide donor and direct acting smooth muscle relaxants, from 4.3-44.4% of alkyl or aryl alcohol, from 60-99.99% of a suitable vehicle and the balance if any, comprising of conventional carriers and adjuvants. In a preferred embodiment, the vehicle is selected from Water, Lactose and other conventional propellants. In a preferred feature, the composition is in the form of an aerosol. Preferably, the size of delivered aerosol is less than 1 micron. In a preferred feature, the MMAD of the aerosol to be inhaled is less than 1 micron or even in nanometers. In a preferred feature, the composition includes conventional surfactants. In a preferred feature, the composition contains one or more of preferred ingredients selected from ascorbic acid, proteins (preferably human serum albumin, heparin or haparin-like substances) and sodium bicarbonate that impart special advantages adding to the efficacy of the formulation. These ingredients by themselves do not produce any useful purpose as detailed before but act in synergy with the essential ingredients of the composition. The present invention also discloses a process for the preparation of a composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia which comprises admixing from 0.1% - 3.6% wt of an active ingredient selected from nitric oxide donor and direct acting smooth muscle relaxants, from 4.3-44.4% of alkyl or aryl alcohol, from 60-99.99% of a suitable vehicle and the balance if any, comprising of conventional carriers and adjuvants. In a preferred embodiment, the said composition is prepared with constituents in the following ratios with respect to the prepared solution: a) nitric oxide donor like nitroglecerine, sodium nitroglecerine, sodium nitroprusside, L-arginie etc. or direct acting smooth muscle relaxants like amlodepine, diliazem and hydralazine in the ratio of 0.1% - 3.6% b) alkyl or aryl alcohol in the ratio of 4.3-44.4% c) glycol/ surfactant in the ration of 0-3.5% d) ascorbic acid in the ratio of 0-1.8% e) sodium chloride in the ration of 0-1.6% f) sodium bicarbonate in the ratio of 0-8.3% g) proteins (HAS/heparin/heparin-like substances in the ratio of 0-8.3% h) water/lactose/propellant: 60-99.99% Detailed description A preparation is disclosed that immediately or quickly reduced pulmonary hypertension and increases blood oxygen upto inhalation as a sub-micro aerosol. It relates to fast management of primary and secondary forms of pulmonary hypertension specifically but without implying any limitation thereof, of all conditions afflicting pulmonary microvasculature and pulmonary parenchyma. Specifically, this is a preparation that provides for local lung delivery of one or more of the direct-acting or nitric oxide donor drugs whose major action is direct vasodilation or through local release of nitric oxide permitting enhancement of blood flow. The preparation my preferably contain adjuvant drugs that enhance local drug delivery of action or provide for sustained action. In the preferred embodiments, direct-acting drugs like hydralazine, nifedipine, diltiazem and amlodepin or nitric oxide donors like nitroglycerine, amyl nitrite, sodium nitroprusside, sodium nitrite or L-arginine are used in presence of preferably isopropyl alcohol, ascorbic acid, permitted surfactants and certain human proteins. The preparation(s), upon inhalation, cause reduction in pulmonary hypertension and increase in oxygen transfer to the blood. The effect may occur almost immediately and persist for an hour or more. Such a formulation is presently not available commercially anywhere for the purpose stated. The formulation contains ingredients responsible for enhancing deposition of the primary drugs into the alveolar space in presence to all other sites of known deposition upon inhalation. The various embodiments of the formulation include the dry powder version, fluid version, MDI versions, vapourized versions and all other versions that may be employed for inhalation of drugs depending upon the chemical composition of the vehicle. ADVANTAGES OF THE PRESENT INVENTION: The presently disclosed invention is a respirable formulation that constitutes a new fast method of management of primary and secondary hypertension, and various diseases where these conditions may occur by association. The present invention will also benefit in all conditions causing hypoxic hypoxemia, particularly those associated with pulmonary hypertension. Treatment of these conditions using local deposition of nitric oxide donor or direct acting smooth muscle relaxants is a new concept. The applicants have found that drugs like nitroglycerine sodium nitroprusside sodium nitrite and the like that act by nitric-oxide release locally are very potent and fast acting in producing vasodilation of pulmonary microcirculation thereby reducing pulmoary hypertension and increasing oxygen transfer to blood. By producing nitric oxide locally in small physiological quantities, problems associated with direct nitric oxide inhalation therapy like toxicity, cost, hospital admission, cumbersome production and monitoring equipment are obviated. The proposed treatment can be given in field conditions with little need of infrastructure or equipment. Still further an advantage is that the new treatment is more effective and has more prolonged or sustained action as compared to nitric oxide inhalation or oxygen inhalation. Yet another advantage of the present invention is higher local deposition and lower systemic dose & effect. Thus the pharmacological effect is higher, systemic side effects are reduced and cost is reduced. Upon nebulization and inhalation of various embodiments of the formulation through medical devices available commercially (like rotacap/ nebumizar MDI technology) the formulation is preferably delivered to the peripheral lung parenchyma, evading significant deposition in oropharynx, trachea and stomach. The active constituents of the aerosol formulation preferably stay in the region of impact for executing their pharmacological action locally. Still further advantage is that is more effective and has more prolonged or sustained action at pulmonary level as compared to the commercial products that are not able to deposit the requisite amount of drug in the alveolar region. Instead, these get deposited in oro-pharynx, stomach to a much larger extent using the same inhalation devices. One of the embodiments of the present invention envisages addition of certain proteins or peptides that impart property of sustained and long-action to the inhaled drug not available with the present inhaler products even though these are meant for action upon tracheobronchial system and not on alveoli, the site of preferred deposition of the present formulation. These proteins or peptides may have thrombolytic and anti-coagulation properties, which help in enhancing blood flow in lung regions where the blood supply may be blocked as a complication. In such complicated cases, inhaled proteins/peptides with thrombolytic activity may prove life-saving. According to a preferred embodiment of this invention, the respirable fluid formulation is prepared by the process comprising of the following steps: To make a non-water based preparation, the active constituents are adsorbed on an approved solid phase (for e.g. lactose) or dissolved in an organic solvent. These act a holding matrix and a vehicle for inhalation by an appropriate delivery system. The preferred active drugs present in the formulation are one or more of the generic nitric oxide donor or producing molecules (for example nitroglycerine, amyl nitrite, sodium nitroprusside, sodium nitrile and L-Arginine hydrochloride) or direct acting smooth muscle relaxants such as hydrazine. Additionally, the composition contains compounds that controls the quantity of the active drugs and their particle size, in flight or otherwise, such as volatile organic compounds, particularly ethers and alcohol, preferably ethyl alcohol or di-ethyl ether. Furthermore, the formulation may contain lactose, water or CFC or non-CFC propellants available commercially in the market as different vehicles for different embodiments of the formulation. The composition may also preferably contain reducing substances like ascorbic acid, bicarbonates preferably sodium bicarbonate to control pH, and carrier proteins or peptides. Furthermore, the composition preferably contains a surfactant, particularly commercial ones already approved for inhalation purposes. All these additional constituents do not act independent of each other; in fact these impart the essential characteristics to the formulation by their synergistic action. One embodiment of the present invention consists of arginine, preferably L-Arginine Hydrochloride (10-7000 miligram) and/or Sodium Nitroprusside and/or hydralazine mixed to 5-40 grams of an alkyl alcohol, preferably ethyl alcohol to which is added 50-95 grams of distilled water. Other preferred constituents of the embodiment include alkyl glycols and ascorbic acid (0-1000 mg), Sodium chloride (0-900 mg), gentistic acid (0-1000 mg), Sodium bicarbonate (0-5000 milligrams) and preferably albumin (human serum albumin) (0-5 gram) and heparin analogues (0 to 5 grams or 0-5000IU equivalent). Though all the constituents can be added to the water base in any order, it is preferred that active drugs may be absorbed to the protein or peptide moiety through procedures already known in the prior art before adding to the final liquid phase. As an alternative, the solid constituents absorbed in protein moiety may be may be lyophilized and reconstituted with liquid component (water, alcohol etc.) at the time of use. One of the preferred embodiments of the formulation is water-based to be used with the regular medical nebulizer apparatus. Other preferred constituents to be added to the water solution include 5-40 grams of alkyl or aryl alcohol, preferably ethyl alcohol, alkyl glycols (upto 2 gram), ascorbic acid (upto 1000 mg), sodium chloride (upto 900 mg), gentisic acid (1000mg), sodium bicarbonate (0-5000 milligrams) and carrier proteins or peptides, preferably albumin of heparin of their analogues (o to 5 grams). Another preferred embodiment of the present invention is adsorption of micronized solid-phase particles of Sodium Nitrite (100 mg-10 grams) with MMAD less than 1 micron to 1-100 grams of solid phase lactose. The resultant solid phase drug-vehicle complex is aliquted before use as Dry Powder Inhalation (DPI) through rotacap or similar devices available commercially. Yet another embodiment of the present invention is in the form of Metered Dose Inhaler where the drug aerosol output at the time of inhalation is such that MMAD is submicronic or even in nanometers. This made possible by use of appropriate maximum pressure in the canister, appropriate higher dilution, appropriate actuator mechanism, canister design and use of spacer available. The preferred vehicle is a low boiling point organic solvent such as propellant 11 (eleven) where the dose of expelled drug per actuation is lesser than 5000 microgram of nitrogycerine, hydralazine or Amyl Nitrite. Ascorbic acid (0-500 microgram) and Sodium bicarbonate (0-100 microgram) and heparin or heparin-like substances (0-400 microgram or 0-1000 IU equivalent) per actuation are also preferably added. In accordance to the preferred embodiments of the present invention, the sequence of predetermined steps and methodology of mixing may be changed in a manner not detrimental to the stability and efficacy of the medical product. Further the MMAD of the inhalable products produced by the various embodiments of the invention are estimated using Laser Scattering and Handerson Impactor instruments as a part of regular quality control embedded within the invention. More further, the beneficial effects of the inhalable products produced by the various embodiments of the invention are estimated and confirmed by such nuclear medicine procedures and blood oxygen estimations. EXAMPLE 1 The present invention will be more apparent from the following experiment which is not intended to limit the scope of the present invention. Weight approximately and accurately 2200 mg of sodium nitrite, 1250 mg of L-Arginine hydrochloride, 500 gm of ascorbic acid and pour in 76. Grams of distilled water. Add 20 grams of ethyl alcohol. The respirable solution so formed is sealed in an airtight container to be opened at the time of use only. MMAD of the product on passing through an appropriate spacer was 0.6 micron. A nuclear medicine Ventilation scan was done on a volunteer using conventional procedures where 300 microCi Tc-99m (volume as little as possible) was inhaled as part of the product. It was compared to a standard nuclear medicine Ventilation scan. Differences in the regional distribution of radioactivity was taken as an indication of invivo efficacy of the product. A Tc-99m MAA nuclear medicine perfusion scan was performed on appropriate individuals before and after treatment with the present invention to confirm increase in pulmonary circulation. Following such confirmations in the laboratory small clinical trials were done on patients using the product where most the advantages as mentioned in another section were confirmed or clarified using appropriate instrumentation. EXAMPLE 2 Weigh approximately and accurately 380 mg of micronized Diltiazem (MMAD less than 1 micron) and 300mg of sodium nitroprusside to be adsorbed uniformly on 100 grams lactose (special grade, available commercially). 1 gram aliquots are prepared to be dispensed as capsules meant for inhalation through appropriate medical devices. EXAMPLE 3 Weight approximately and accurately 300 mg of nitroglycerine and 50 mg of nifedipine and mix in 50 grams of propellant - 11 (commercially available) in controlled conditions and stored under pressure in appropriate cannisters. Aliquots of 100-300 microliters are to be dispensed directly or through appropriate spacers. The essential quality control measure embedded in the procedure itself is confirmation of MMAD less than 1 micron size. We claim: 1. A composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia which comprises from 0.1% - 3.6% wt of an active ingredient selected from nitric oxide donor and direct acting smooth muscle relaxants, from 4.3-44.4% of alkyl or aryl alcohol, from 60-99.99% of a suitable vehicle and the balance if any, comprising of conventional carriers and adjuvants. 2. A composition as claimed in claim 1 wherein the vehicle is selected from water, lactose and other conventional propellants. 3. A composition as claimed in claim 1 or 2 in the form of an aerosol 4. A composition as claimed in claim 1 wherein the size of delivered aerosol is less than 1 micron. 5. A composition as claimed in claim 3 or 4 wherein the MMAD of the aerosol to be inhaled is less than 1 micron or even in nanometers. 6. A composition as claimed in claim 5 wherein it further includes conventional surfactants. 7. A composition as claimed in any preceding claim wherein it comprises one or more of preferred ingredients selected from ascorbic acid, proteins (preferably human serum albumin, heparin or haparin-like substances) and sodium bicarbonate that impart special advantages adding to the efficacy of the formulation. 8. A composition as claimed in any preceding claim comprising: a) nitric oxide donor like nitroglecerine, sodium nitroglecerine, sodium nitroprusside, L-arginie etc. or direct acting smooth muscle relaxants like amlodepine, diliazem and hydralazine in the ratio of 0.1% - 3.6% b) alkyl or aryl alcohol in the ratio of 4.3-44.4% c) glycol/ surfactant in the ration of 0-3.5% d) ascorbic acid in the ratio of 0-1.8% e) sodium chloride in the ration of 0-1.6% fj sodium bicarbonate in the ratio of 0-8.3% g) proteins (HAS/heparin/heparin-like substances in the ratio of 0-8.3% h) water/lactose/propellant: 60-99.99% 9. A process for the preparation of a composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia which comprises admixing from 0.1% - 3.6% wt of an active ingredient selected from nitric oxide donor and direct acting smooth muscle relaxants, from 4.3-44.4% of alkyl or aryl alcohol, from 60-99.99% of a suitable vehicle and the balance if any, comprising of conventional carriers and adjuvants. 10. A process as claimed in claim 9 which comprises mixing: a) nitric oxide donor like nitroglecerine, sodium nitroglecerine, sodium nitroprusside, L-arginie etc. or direct acting smooth muscle relaxants like amlodepine, diliazem and hydralazine in the ratio of 0.1% - 3.6% b) alkyl or aryl alcohol in the ratio of 4.3-44.4% c) glycol/ surfactant in the ration of 0-3.5% d) ascorbic acid in the ratio of 0-1.8% e) sodium chloride in the ration of 0-1.6% f) sodium bicarbonate in the ratio of 0-8.3% g) proteins (HAS/heparin/heparin-like substances in the ratio of 0-8.3% h) water/lactose/propellant: 60-99.99% 11. A composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia substantially as described herein with reference torn the foregoing examples. 12. A process for the preparation of a composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia substantially as described herein with reference to the foregoing examples.

Full Text

FILED OF THE INVENTION
The present invention relates to a composition for use in the immediate or quick reduction of pulmonary hypertension. More, particularly, the present invention relates to a composition for use in the immediate or quick reduction of pulmonary hypertension and increases blood oxygen. In particular, the present invention relates to a nitric oxide donor based respiratory composition for management of pulmonary hypertension and other hypoxic hypoxema. The present invention also relates to a process for the preparation of nitric oxide donor based respiratory composition and the use thereof in the treatment and management of pulmonary hypertension and other hypoxic hypoxema.. PRIOR ART
Pulmonary hypertension generally relates to pulmonary vasoconstriction, usually diffuse in pulmonary microcirculation leading to increase in pulmonary vascular resistance and pulmonary artery pressure.
Pulmonary hypertension can be primary (cause unknown) or secondary to a number of lung diseases. Primary pulmonary hypertension has no successful treatment and leads to mortality in the long run. Secondary pulmonary hypertension almost always complicates a number of respiratory diseases like chronic obstructive airway disease and its variants, bronchial asthma, diffuse tuberculosis, emphysema, interstitial lung disease and Adult Respiratory Distress Syndrome. Still further, it is associated with high altitude, acute and chronic mountain sickness and high altitude pulmonary edema.
Pulmonary hypertension, particularly with hypoxemia may become so severe as to cause death or severe incapacitation.. A further complication is pulmonary edema, pulmonary hemorrhages and hemoptysis. Still another complication of pulmonary hypertension is right-sided heart enlargement and failure.
The medical management methods known in the art are inadequate to meet the challenge of this common and frequently a fatal problem. The treatments are either slow, relatively ineffective, expensive, cumbersome, or a combination thereof.
One of the main treatment modalities is systemically delivered vasodilators that attempt to dilate the pulmonary blood vessels by administration of the drug orally or by injection. Drugs like prazocin, nifedipine, phentolamine and sildenafil have been used for the purpose.
The main problem with systemic delivery is that a high dosage in the circulation is required for the desired effect because the drug is distributed throughout the body fluids. The very usage causes side effects like hypertension, significant palpitation and limits the use of this treatment.
The known treatments also limit the duration of treatment to a few days or weeks only while most of the diseases with which pulmonary hypertension is associated are chronic in nature and may require treatment for years or even for life.
Furthermore, systemic vasodilator therapy becomes reversed for very severe cases only while most patients have mild to moderate problem. Also, the effect is slow and delayed and not suited for conditions where fast action is desired.
Systemic vasodilators are therefore, now considered an inadequate treatment in pulmonary hypertension but continue to be given in absence of a better treatment choice.
For fast management of pulmonary hypertension, particularly with hypoxemia, oxygen inhalation is prescribed. However, the therapy does not treat pulmonary hypertension; it only reduces its effect. Also, it can only be given only for short periods. Furthermore, it is expensive and mostly requires infrastructural facilities for administration. It immobilized the patient for the period of therapy. Thus, it is useful only as an adjunct treatment for a short period.
Yet another line of treatment is Nitric Oxide inhalation therapy. However, the therapy can only be given in severe cases and is not suitable for prolonged or continuous use. Secondly, it is expensive, and not indegenously available even in most of the super-specialty hospitals in India. It is essentially a hospital-based treatment and can be hazardous. Further, it confines the patient for the period of therapy. Thus, it is useful only for short-duration treatment and cannot be used routinely.
OBJECTS OF THE INVENTION
Thus, considering the widespread nature of the disease (primary or secondary pulmonary hypertension), its fatal or incapacitating nature, and further considering the inadequacy of the present line of management with respect to control or cure, side effects, cost-effectiveness, patient comfort or availability, there is an urgent need for a new treatment methodology for fast and effective treatment of this serious condition.
Accordingly, it is an important object of the present invention to provide a composition for use in the immediate or quick reduction of pulmonary hypertension.
It is another object of the present invention to provide a composition for use in the immediate or quick reduction of pulmonary hypertension and increases blood oxygen.
It is yet another object of the present invention to provide a nitric oxide donor based respiratory composition for management of pulmonary hypertension and other hypoxic hypoxema.
It is yet another object of the present invention to provide a process for the preparation of nitric oxide donor based respiratory composition and the use thereof in the treatment and management of pulmonary hypertension and other hypoxic hypoxema.
It is yet another object of the present invention to provide a novel composition and process of its preparation that can be used as a fast method for management of primary pulmonary hypertension, secondary pulmonary hypertension and hypoxic hypoxemic states, but without implying any limitation of its use.
It is yet another object of the present invention to provide a composition that increases the pulmonary blood circulation and oxygen transfer to blood by either acting directly on the smooth muscles of pulmonary microvasculature or by producing nitric oxide locally that in turn causes smooth muscle relaxation of pulmonary microvasculature.
It is yet another object of the present invention to provide a composition that help in reduce the size of the aerosized drug particles prior to inhalation and make it possible for the various embodiments of the composition to be given through various
types of inhalation devices to produce dry or wet inhalable aerosolized drug particle of very small dimensions.
SUMMARY OF THE INVENTION
In view of the severe limitations of the current treatment methods as exposed above, the present inventors have given great emphasis in developing a new strategy for treating or preventing pulmonary hypertension that may be very effective in quick control of disease and its symptoms and complications. It is also cost-effective, non-hazardous, capable of being used with minimal infrastructure needs, and easy to perform at field level.
The concept used by the present invention that of inhalation therapy for alveolar deposition (ITAD) through nebulization, is a novel concept and the formulation that has been developed based on the concepts is a novel formulation.
Accordingly, the present invention provides a composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia which comprises from 0.1% - 3.6% wt of an active ingredient selected from nitric oxide donor and direct acting smooth muscle relaxants, from 4.3-44.4% of alkyl or aryl alcohol, from 60-99.99% of a suitable vehicle and the balance if any, comprising of conventional carriers and adjuvants.
In a preferred embodiment, the vehicle is selected from Water, Lactose and other conventional propellants.
In a preferred feature, the composition is in the form of an aerosol. Preferably, the size of delivered aerosol is less than 1 micron.
In a preferred feature, the MMAD of the aerosol to be inhaled is less than 1 micron or even in nanometers.
In a preferred feature, the composition includes conventional surfactants.
In a preferred feature, the composition contains one or more of preferred ingredients selected from ascorbic acid, proteins (preferably human serum albumin, heparin or haparin-like substances) and sodium bicarbonate that impart special
advantages adding to the efficacy of the formulation. These ingredients by themselves do not produce any useful purpose as detailed before but act in synergy with the essential ingredients of the composition.
The present invention also discloses a process for the preparation of a composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia which comprises admixing from 0.1% - 3.6% wt of an active ingredient selected from nitric oxide donor and direct acting smooth muscle relaxants, from 4.3-44.4% of alkyl or aryl alcohol, from 60-99.99% of a suitable vehicle and the balance if any, comprising of conventional carriers and adjuvants.
In a preferred embodiment, the said composition is prepared with constituents in the following ratios with respect to the prepared solution:
a) nitric oxide donor like nitroglecerine, sodium nitroglecerine, sodium nitroprusside, L-arginie etc. or direct acting smooth muscle relaxants like amlodepine, diliazem and hydralazine in the ratio of 0.1% - 3.6%
b) alkyl or aryl alcohol in the ratio of 4.3-44.4%
c) glycol/ surfactant in the ration of 0-3.5%
d) ascorbic acid in the ratio of 0-1.8%
e) sodium chloride in the ration of 0-1.6%
f) sodium bicarbonate in the ratio of 0-8.3%
g) proteins (HAS/heparin/heparin-like substances in the ratio of 0-8.3%
h) water/lactose/propellant: 60-99.99%
Detailed description
A preparation is disclosed that immediately or quickly reduced pulmonary hypertension and increases blood oxygen upto inhalation as a sub-micro aerosol. It relates to fast management of primary and secondary forms of pulmonary hypertension specifically but without implying any limitation thereof, of all conditions afflicting pulmonary microvasculature and pulmonary parenchyma. Specifically, this is a preparation that provides for local lung delivery of one or more of the direct-acting or nitric oxide donor drugs whose major action is direct vasodilation or through local release of nitric oxide permitting enhancement of blood flow. The preparation my
preferably contain adjuvant drugs that enhance local drug delivery of action or provide for sustained action. In the preferred embodiments, direct-acting drugs like hydralazine, nifedipine, diltiazem and amlodepin or nitric oxide donors like nitroglycerine, amyl nitrite, sodium nitroprusside, sodium nitrite or L-arginine are used in presence of preferably isopropyl alcohol, ascorbic acid, permitted surfactants and certain human proteins. The preparation(s), upon inhalation, cause reduction in pulmonary hypertension and increase in oxygen transfer to the blood. The effect may occur almost immediately and persist for an hour or more. Such a formulation is presently not available commercially anywhere for the purpose stated.
The formulation contains ingredients responsible for enhancing deposition of the primary drugs into the alveolar space in presence to all other sites of known deposition upon inhalation. The various embodiments of the formulation include the dry powder version, fluid version, MDI versions, vapourized versions and all other versions that may be employed for inhalation of drugs depending upon the chemical composition of the vehicle. ADVANTAGES OF THE PRESENT INVENTION:
The presently disclosed invention is a respirable formulation that constitutes a new fast method of management of primary and secondary hypertension, and various diseases where these conditions may occur by association. The present invention will also benefit in all conditions causing hypoxic hypoxemia, particularly those associated with pulmonary hypertension. Treatment of these conditions using local deposition of nitric oxide donor or direct acting smooth muscle relaxants is a new concept. The applicants have found that drugs like nitroglycerine sodium nitroprusside sodium nitrite and the like that act by nitric-oxide release locally are very potent and fast acting in producing vasodilation of pulmonary microcirculation thereby reducing pulmoary hypertension and increasing oxygen transfer to blood.
By producing nitric oxide locally in small physiological quantities, problems associated with direct nitric oxide inhalation therapy like toxicity, cost, hospital admission, cumbersome production and monitoring equipment are obviated. The
proposed treatment can be given in field conditions with little need of infrastructure or equipment.
Still further an advantage is that the new treatment is more effective and has more prolonged or sustained action as compared to nitric oxide inhalation or oxygen inhalation.
Yet another advantage of the present invention is higher local deposition and lower systemic dose & effect. Thus the pharmacological effect is higher, systemic side effects are reduced and cost is reduced.
Upon nebulization and inhalation of various embodiments of the formulation through medical devices available commercially (like rotacap/ nebumizar MDI technology) the formulation is preferably delivered to the peripheral lung parenchyma, evading significant deposition in oropharynx, trachea and stomach. The active constituents of the aerosol formulation preferably stay in the region of impact for executing their pharmacological action locally.
Still further advantage is that is more effective and has more prolonged or sustained action at pulmonary level as compared to the commercial products that are not able to deposit the requisite amount of drug in the alveolar region. Instead, these get deposited in oro-pharynx, stomach to a much larger extent using the same inhalation devices.
One of the embodiments of the present invention envisages addition of certain proteins or peptides that impart property of sustained and long-action to the inhaled drug not available with the present inhaler products even though these are meant for action upon tracheobronchial system and not on alveoli, the site of preferred deposition of the present formulation. These proteins or peptides may have thrombolytic and anti-coagulation properties, which help in enhancing blood flow in lung regions where the blood supply may be blocked as a complication. In such complicated cases, inhaled proteins/peptides with thrombolytic activity may prove life-saving.
According to a preferred embodiment of this invention, the respirable fluid formulation is prepared by the process comprising of the following steps:
To make a non-water based preparation, the active constituents are adsorbed on an approved solid phase (for e.g. lactose) or dissolved in an organic solvent. These act a holding matrix and a vehicle for inhalation by an appropriate delivery system.
The preferred active drugs present in the formulation are one or more of the generic nitric oxide donor or producing molecules (for example nitroglycerine, amyl nitrite, sodium nitroprusside, sodium nitrile and L-Arginine hydrochloride) or direct acting smooth muscle relaxants such as hydrazine. Additionally, the composition contains compounds that controls the quantity of the active drugs and their particle size, in flight or otherwise, such as volatile organic compounds, particularly ethers and alcohol, preferably ethyl alcohol or di-ethyl ether. Furthermore, the formulation may contain lactose, water or CFC or non-CFC propellants available commercially in the market as different vehicles for different embodiments of the formulation. The composition may also preferably contain reducing substances like ascorbic acid, bicarbonates preferably sodium bicarbonate to control pH, and carrier proteins or peptides. Furthermore, the composition preferably contains a surfactant, particularly commercial ones already approved for inhalation purposes. All these additional constituents do not act independent of each other; in fact these impart the essential characteristics to the formulation by their synergistic action.
One embodiment of the present invention consists of arginine, preferably L-Arginine Hydrochloride (10-7000 miligram) and/or Sodium Nitroprusside and/or hydralazine mixed to 5-40 grams of an alkyl alcohol, preferably ethyl alcohol to which is added 50-95 grams of distilled water. Other preferred constituents of the embodiment include alkyl glycols and ascorbic acid (0-1000 mg), Sodium chloride (0-900 mg), gentistic acid (0-1000 mg), Sodium bicarbonate (0-5000 milligrams) and preferably albumin (human serum albumin) (0-5 gram) and heparin analogues (0 to 5 grams or 0-5000IU equivalent). Though all the constituents can be added to the water base in any order, it is preferred that active drugs may be absorbed to the protein or peptide moiety through procedures already known in the prior art before adding to the final liquid phase. As an alternative, the solid constituents absorbed in protein
moiety may be may be lyophilized and reconstituted with liquid component (water, alcohol etc.) at the time of use.
One of the preferred embodiments of the formulation is water-based to be used with the regular medical nebulizer apparatus. Other preferred constituents to be added to the water solution include 5-40 grams of alkyl or aryl alcohol, preferably ethyl alcohol, alkyl glycols (upto 2 gram), ascorbic acid (upto 1000 mg), sodium chloride (upto 900 mg), gentisic acid (1000mg), sodium bicarbonate (0-5000 milligrams) and carrier proteins or peptides, preferably albumin of heparin of their analogues (o to 5 grams).
Another preferred embodiment of the present invention is adsorption of micronized solid-phase particles of Sodium Nitrite (100 mg-10 grams) with MMAD less than 1 micron to 1-100 grams of solid phase lactose. The resultant solid phase drug-vehicle complex is aliquted before use as Dry Powder Inhalation (DPI) through rotacap or similar devices available commercially.
Yet another embodiment of the present invention is in the form of Metered Dose Inhaler where the drug aerosol output at the time of inhalation is such that MMAD is submicronic or even in nanometers. This made possible by use of appropriate maximum pressure in the canister, appropriate higher dilution, appropriate actuator mechanism, canister design and use of spacer available. The preferred vehicle is a low boiling point organic solvent such as propellant 11 (eleven) where the dose of expelled drug per actuation is lesser than 5000 microgram of nitrogycerine, hydralazine or Amyl Nitrite. Ascorbic acid (0-500 microgram) and Sodium bicarbonate (0-100 microgram) and heparin or heparin-like substances (0-400 microgram or 0-1000 IU equivalent) per actuation are also preferably added.
In accordance to the preferred embodiments of the present invention, the sequence of predetermined steps and methodology of mixing may be changed in a manner not detrimental to the stability and efficacy of the medical product.
Further the MMAD of the inhalable products produced by the various embodiments of the invention are estimated using Laser Scattering and Handerson Impactor instruments as a part of regular quality control embedded within the
invention. More further, the beneficial effects of the inhalable products produced by
the various embodiments of the invention are estimated and confirmed by such
nuclear medicine procedures and blood oxygen estimations.
EXAMPLE 1
The present invention will be more apparent from the following experiment which is
not intended to limit the scope of the present invention.
Weight approximately and accurately 2200 mg of sodium nitrite, 1250 mg of L-Arginine hydrochloride, 500 gm of ascorbic acid and pour in 76. Grams of distilled water. Add 20 grams of ethyl alcohol. The respirable solution so formed is sealed in an airtight container to be opened at the time of use only.
MMAD of the product on passing through an appropriate spacer was 0.6 micron. A nuclear medicine Ventilation scan was done on a volunteer using conventional procedures where 300 microCi Tc-99m (volume as little as possible) was inhaled as part of the product. It was compared to a standard nuclear medicine Ventilation scan. Differences in the regional distribution of radioactivity was taken as an indication of invivo efficacy of the product. A Tc-99m MAA nuclear medicine perfusion scan was performed on appropriate individuals before and after treatment with the present invention to confirm increase in pulmonary circulation. Following such confirmations in the laboratory small clinical trials were done on patients using the product where most the advantages as mentioned in another section were confirmed or clarified using appropriate instrumentation. EXAMPLE 2
Weigh approximately and accurately 380 mg of micronized Diltiazem (MMAD less than 1 micron) and 300mg of sodium nitroprusside to be adsorbed uniformly on 100 grams lactose (special grade, available commercially). 1 gram aliquots are prepared to be dispensed as capsules meant for inhalation through appropriate medical devices.
EXAMPLE 3
Weight approximately and accurately 300 mg of nitroglycerine and 50 mg of nifedipine and mix in 50 grams of propellant - 11 (commercially available) in controlled conditions and stored under pressure in appropriate cannisters. Aliquots of 100-300 microliters are to be dispensed directly or through appropriate spacers.
The essential quality control measure embedded in the procedure itself is confirmation of MMAD less than 1 micron size.

We claim:
1. A composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia which comprises from 0.1% - 3.6% wt of an active ingredient selected from nitric oxide donor and direct acting smooth muscle relaxants, from 4.3-44.4% of alkyl or aryl alcohol, from 60-99.99% of a suitable vehicle and the balance if any, comprising of conventional carriers and adjuvants.
2. A composition as claimed in claim 1 wherein the vehicle is selected from water, lactose and other conventional propellants.
3. A composition as claimed in claim 1 or 2 in the form of an aerosol
4. A composition as claimed in claim 1 wherein the size of delivered aerosol is less than 1 micron.
5. A composition as claimed in claim 3 or 4 wherein the MMAD of the aerosol to be inhaled is less than 1 micron or even in nanometers.
6. A composition as claimed in claim 5 wherein it further includes conventional surfactants.
7. A composition as claimed in any preceding claim wherein it comprises one or more of preferred ingredients selected from ascorbic acid, proteins (preferably human serum albumin, heparin or haparin-like substances) and sodium bicarbonate that impart special advantages adding to the efficacy of the formulation.
8. A composition as claimed in any preceding claim comprising:

a) nitric oxide donor like nitroglecerine, sodium nitroglecerine, sodium nitroprusside, L-arginie etc. or direct acting smooth muscle relaxants like amlodepine, diliazem and hydralazine in the ratio of 0.1% - 3.6%
b) alkyl or aryl alcohol in the ratio of 4.3-44.4%
c) glycol/ surfactant in the ration of 0-3.5%
d) ascorbic acid in the ratio of 0-1.8%
e) sodium chloride in the ration of 0-1.6%
fj sodium bicarbonate in the ratio of 0-8.3%
g) proteins (HAS/heparin/heparin-like substances in the ratio of 0-8.3%
h) water/lactose/propellant: 60-99.99%
9. A process for the preparation of a composition for use in the treatment and management of pulmonary hypertension and other hypoxic hypoxemia which comprises admixing from 0.1% - 3.6% wt of an active ingredient selected from nitric oxide donor and direct acting smooth muscle relaxants, from 4.3-44.4% of alkyl or aryl alcohol, from 60-99.99% of a suitable vehicle and the balance if any, comprising of conventional carriers and adjuvants.
10. A process as claimed in claim 9 which comprises mixing:

a) nitric oxide donor like nitroglecerine, sodium nitroglecerine, sodium nitroprusside, L-arginie etc. or direct acting smooth muscle relaxants like amlodepine, diliazem and hydralazine in the ratio of 0.1% - 3.6%
b) alkyl or aryl alcohol in the ratio of 4.3-44.4%
c) glycol/ surfactant in the ration of 0-3.5%
d) ascorbic acid in the ratio of 0-1.8%
e) sodium chloride in the ration of 0-1.6%
f) sodium bicarbonate in the ratio of 0-8.3%
g) proteins (HAS/heparin/heparin-like substances in the ratio of 0-8.3% h) water/lactose/propellant: 60-99.99%
11. A composition for use in the treatment and management of pulmonary
hypertension and other hypoxic hypoxemia substantially as described herein with
reference torn the foregoing examples.
12. A process for the preparation of a composition for use in the treatment and
management of pulmonary hypertension and other hypoxic hypoxemia substantially
as described herein with reference to the foregoing examples.

Documents:

1438-del-2005-Abstract-(19-12-2012).pdf

1438-del-2005-abstract.pdf

1438-del-2005-Claims-(19-12-2012).pdf

1438-del-2005-claims.pdf

1438-del-2005-Correspondence Others-(06-06-2011).pdf

1438-del-2005-Correspondence Others-(09-05-2011).pdf

1438-del-2005-Correspondence Others-(19-12-2012).pdf

1438-del-2005-correspondence-others.pdf

1438-del-2005-correspondence-po.pdf

1438-del-2005-Description (Complete)-(19-12-2012).pdf

1438-del-2005-description (complete).pdf

1438-del-2005-form-1.pdf

1438-del-2005-form-18.pdf

1438-del-2005-Form-2-(19-12-2012).pdf

1438-del-2005-form-2.pdf

1438-del-2005-form-3.pdf

1438-del-2005-GPA-(06-06-2011).pdf

1438-del-2005-gpa.pdf

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Patent Number

258190

Indian Patent Application Number

1438/DEL/2005

PG Journal Number

51/2013

Publication Date

20-Dec-2013

Grant Date

13-Dec-2013

Date of Filing

03-Jun-2005

Name of Patentee

DIRECTOR GENERAL, DEFENCE RESEARCH & DEVELOPMENT ORGANISATION

Applicant Address

MINISTRY OF DEFENCE, GOVERNMENT OF INDIA, WEST BLOCK-VII, WING-I, SECTOR-1, R.K. PURAM, NEW DELHI-110066

Inventors:

#	Inventor's Name	Inventor's Address
1	WILLIAM SCLVAMURTHY	SENA BHAWAN, NEW DELHI
2	ASSEM BHATNAGAR	INMAS, DELHI
3	PRADEEP KUMAR CHUGH	INMAS, DELHI
4	RAVI KASHYAP	INMAS, DELHI
5	AJAY KUMAR SINGH	INMAS, DELHI

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA