Patent Application
20230263777
The present invention provides a stable solid pharmaceutical composition comprising Azilsartan or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient(s); optionally, the said composition further comprises a diuretic.
Azilsartan is an angiotensin II receptor antagonist, which blocks the vasoconstriction activity of angiotensin II by selectively blocking the binding of angiotensin II and vascular smooth muscle AT1 receptor. Angiotensin II receptor antagonists are used in the management of hypertension, to lower the blood pressure. The potassium compound of Azilsartan medoxomil has the chemical name (5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl 2-ethoxy-1-({4-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylate and its structural formula is as follows.
Azilsartan kamedoxomil is a white to nearly white powder with a molecular weight of 606.62. It is practically insoluble in water and freely soluble in methanol.
Diuretics are orally administered in the treatment of hypertension and edema. Well known diuretics are thiazides which are known moderately potent diuretics and exert their diuretic effect by reducing the reabsorbtion of electrolytes from the renal tubules, thereby increasing the excretion of sodium and chloride ions, and consequently of water.
Chlorthalidone, also known as Chlortalidone, is a diuretic medication used to treat high blood pressure, swelling including that due to heart failure, liver failure, and nephrotic syndrome, diabetes insipidus, and renal tubular acidosis and its structural formula is as follows.
In high blood pressure use of Chlorthalidone is a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days.
It is known that co-administration of an angiotensin II receptor antagonist and a diuretic is an effective therapy for the prevention or treatment of hypertension.
Azilsartan kamedoxomil is marketed as tablets for oral administration under the brand name EDARBI® in strengths of 40 and 80 mg equivalent to Azilsartan medoxomil.
Azilsartan kamedoxomil in combination with Chlorthalidone is marketed as tablets for oral administration under the brand name EDARBYCLOR® in strengths of Eq 40 mg Medoxomil; 12.5 mg and EQ 40 mg Medoxomil; 25 mg.
U.S. Pat. No. 7,157,584 B1 describes Azilsartan compound specifically and it's salt.
U.S. Pat. No. 9,066,936 B1 describes composition comprising Azilsartan, a pH controlling agent which provides a pH of 3 to 5 when dissolved or suspended in water at a cons. 1% w/v at 25 degree C.
U.S. Pat. No. 9,169,238 B1 relates to a solid preparation comprising a first part comprising Azilsartan and pH controlling agent and a second part comprising Chlorthalidone which is obtained by separate granulation; pH is 2 to 5.
However, there is need to develop stable pharmaceutical composition comprising a specific angiotensin II receptor antagonist, such as compound of formula I with specific pH optionally in combination with diuretic selected from thiazide derivatives such as compound of formula II. The main challenge is to provide stable pharmaceutical composition comprising compound of formula I either alone or in combination with diuretic when the pH range is more than 5 which has an adequate content uniformity causing a good dispersion upon oral administration and high bioavailability with improved manufacturing processes and stability and a robust final dosage form for their preparation and use thereof.
Considering pH range greater than 5, composition of various drugs have been investigated and it has been found that a pharmaceutical composition containing a specific angiotensin II receptor antagonist, such as compound of formula I, and optionally one or more diuretics selected from thiazide derivatives such as compound of formula II exerts excellent anti-hypertensive effects and hence is useful as a preventative and/or therapeutic agent for hypertension.
The present invention relates to a stable solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s); optionally the composition further comprises one or more diuretics. It further relates to a process for preparation of the said composition, wherein the said composition is used in the treatment of hypertension by orally administering to a subject in need thereof.
In one general aspect, the present invention provides a stable solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s); wherein the composition is used in the treatment of hypertension by orally administering to a subject in need thereof.
In another general aspect, the present invention provides a stable solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s); wherein one or more pharmaceutically acceptable excipient(s) include but are not limited to fillers, diluents, binders, disintegrants, coating agents, glidants, surfactants, pH modifiers, lubricants, vehicle, polymer or coating system and the like.
In another general aspect, the present invention provides use of the potassium compound of Azilsartan medoxomil having compound of formula I and chemical name (5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl 2-ethoxy-1-({4-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylate, in the treatment of hypertension in a subject in need thereof.
In another general aspect, the present invention provides a process for preparing a solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s); wherein the composition is used in the treatment of hypertension by orally administering to a subject in need thereof.
In another general aspect, the present invention provides stable solid pharmaceutical composition comprising Azilsartan kamedoxomil and one or more pharmaceutically acceptable excipient(s), wherein 1% w/v solution of acid and base combination results in pH above 5, specifically in the range from 5.1 to 7.0.
In another general aspect, the present invention provides stable solid pharmaceutical composition comprising Azilsartan kamedoxomil and one or more pharmaceutically acceptable excipient(s), wherein 1% w/v solution of acid and base combination used in the present composition, gives pH range from about 5.1 to about 7.0 when dissolved or suspended in water; wherein the said composition is used in the treatment of hypertension by orally administering to a subject in need thereof.
In another general aspect, the present invention provides stable solid pharmaceutical composition comprising Azilsartan or its pharmaceutically acceptable salt thereof; wherein the said composition further comprises a diuretic; specifically the diuretic includes thiazide diuretics; more specifically the thiazide diuretic is Chlorthalidone.
In another general aspect, the present invention provides stable solid composition comprising combination of Azilsartan kamedoxomil and Chlorthalidone and one or more pharmaceutically acceptable excipient(s), wherein the composition is administered orally for the treatment of lowering the blood pressure in a subject in need thereof.
In another general aspect, the present invention provides a process for preparing a solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s); wherein the said composition further comprises a diuretic; specifically the diuretic includes thiazide diuretics; more specifically the thiazide diuretic is Chlorthalidone.
It should be understood that the detailed description and specific examples, while indicating embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art. One skilled in the art, based upon the definitions herein, may utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Unless otherwise defined, all the terms used herein, including the technical and scientific terms, have the meaning as that generally understood by one of ordinary skill in the art to which the present invention relates.
The general terms used hereinbefore and hereinafter preferably have the following meanings within the context of this disclosure, unless otherwise indicated. Thus, the definitions of the general terms as used in the context of the present invention are provided herein below:
The terms “a”, “an” and “the” refers to “one or more” when used in the subject specification, including the claims. Thus, for example, reference to “a disease” or “a condition” includes a plurality of diseases or disorders.
It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
As used herein the term “pharmaceutically acceptable” is meant that the carrier, diluent, excipient(s), and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof. “Pharmaceutically acceptable” also means that the compositions or dosage forms are within the scope of sound medical judgment, suitable for use for an animal or human without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term “pharmaceutical combination” or “combination” as used herein means the combined administration of the therapeutic agents. In the context of the present invention, the therapeutic agents include an angiotensin II receptor blocker (ARB) and a diuretic that can be administered independently at the same time or separately within time intervals such that these time intervals allow the combination partners to exhibit a synergistic effect.
As used herein, the term “pH” is a measure of hydrogen ion concentration, as commonly used in the art. Customarily, the pH provides a measure on a scale from 0 to 14 of the acidity or alkalinity of a solution.
As used herein, the term “about” refers to a range of values ±10% of a specified value.
As used in this disclosure, “API” or “API-01” or “API-02” is an abbreviation for active pharmaceutical ingredient. API means, any substance or compound to be used in the manufacture of a drug product. Such substances furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body. In the context of the present invention, API-01 and API-02 refer to the active pharmaceutical ingredient “Azilsartan or its salt” and “thiazide diuretic such as Chlorthalidone” respectively.
Within the context of the present invention and as used herein, unless indicated otherwise, references to total weight of the pharmaceutical composition refers to the total weight of the active agent(s) and pharmaceutically acceptable excipient(s).
Within the context of the present invention and as used herein the term “subject” refers to an animal, preferably a mammal, and most preferably a human. In the context of the present invention, the term “mammal” is used interchangeably with the term “patient” or “subject”. In the context of the present invention, the phrase “a subject in need thereof” means a subject (patient) in need of the treatment of a disease or disorder for which drug substance is used.
Within the context of the present invention and as used herein the term ‘diluent’ refers to an agent used as filler in order to achieve the desired composition volume or weight. The diluent may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds. Diluents are often added to tablet formulations to provide better tablet properties such as to improve cohesion, to allow direct compression manufacturing, to enhance flow and to adjust weight of tablet as per die capacity. Diluents are generally classified into three categories namely organic, inorganic and co-processed diluents. The organic diluents include but are not limited to, lactose such as α-lactose monohydrate, spray dried lactose and anhydrous lactose, starch such as potato starch, corn starch or maize starch, and pregelatinized starch, icing sugar with starch, sucrose, mannitol, sorbitol, cellulose such as powdered cellulose and microcrystalline cellulose. The inorganic diluents include but are not limited to calcium phosphates such as anhydrous dibasic calcium phosphate, dibasic calcium phosphate and tribasic calcium phosphate. Some of the insoluble diluents include but are not limited to starch, powdered cellulose, microcrystalline cellulose, calcium phosphate and the like. Some of the soluble diluents include but are not limited to lactose, sucrose, mannitol, sorbitol and the like.
Binders are dry powders or liquid which are added during granulation process to promote granules and cohesiveness. Binders are, but not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose, gelatin, liquid glucose, corn starch or maize starch, pregelatinized starch, hydrocolloids, sugars, polyvinyl pyrrolidone, sodium alginate, acacia, alginic acid, tragacanth, xanthan, used either alone or combinations thereof.
Disintegrant as used in herein refers to any material that facilitates the break-up of a tablet prepared from the composition when placed in contact with an aqueous medium. Suitable disintegrants include, but are not limited to, crospovidone, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, carboxymethylcellulose sodium or calcium, croscarmellose sodium, pregelatinized starch, polacrilin potassium, low-substituted hydroxypropylcellulose, sodium or calcium alginate, agar, guar gum, chitosan, alginic acid and mixtures thereof.
Glidants improve the flowability of the composition. Exemplary glidants are, but not limited to, fumed silica (colloidal silicon dioxide), colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, magnesium stearate, magnesium carbonate, mixtures thereof and the like.
Lubricants are added in small quantities to tablet formulations to improve certain processing characteristics. The role of the lubricants is to ensure that tablet formation and ejection can occur with low friction between the tablet ingredients and the die walls of the tableting machine. Lubricant prevents sticking to punch faces and enhances product flow by reducing interparticulate friction. The lubricant may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds. Lubricants are, but not limited to sodium oleate, sodium stearate, sodium benzoate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like.
Generally, suitable surfactants include anionic, cationic, and nonionic surfactants, or combinations thereof. In one aspect, such surfactants are nonionic and/or anionic surfactants. In one aspect, the concentration of surfactant is about 0.1% w/w to about 2% w/w;
One or more of these excipient(s) can be selected and used by the artisan having regard to the particular desired properties of the solid dosage form. The amount of each type of excipient employed, e.g. diluent, binder, disintegrant, pH adjusting agent, glidant and lubricant may vary within ranges conventional in the art.
Coating materials are polymeric or non-polymeric, but not limited to, sugars, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, sodium carboxylmethylcellulose, coatings based on methacrylic acid and its esters, such as Eudragit®, mixtures thereof and the like. As alternatives for the above coating materials, sometimes pre-formulated coating products such as those sold as OPADRY™ will be used, for example Opadry White or Opadry Green. The products sold in a solid form require only mixing with a liquid before use. Alternatively, film-forming agents may be applied as powders, using suitable powder coating equipment known in the art.
The vehicle used to prepare the dispersion may be selected from water or its mixture with other organic solvent such as ethanol, methanol, isopropyl alcohol and ether.
Suitable pharmaceutical compositions include, but are not limited to, capsules, tablets, granules, powders and unit dose pockets. Preferably the oral pharmaceutical composition is a tablet.
In an embodiment, the present invention provides a stable solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s) thereof; optionally the composition comprises one or more diuretics. The invention further relates to a method of treating hypertension in a subject in need thereof, wherein the said composition is administered orally.
In another embodiment, the present invention relates to a stable solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s); wherein one or more pharmaceutically acceptable excipient(s) present in the oral dosage form include but are not limited to fillers, diluents, binders, disintegrants, coating agents, glidants, surfactants, pH modifiers or pH adjusting agents, lubricants, vehicle, and the like.
In another embodiment, the concentration of surfactant in the composition is present in the range from about 0.1% w/w to about 2% w/w.
In another embodiment, the concentration of pH adjusting agent(s) in the composition is present in the range from about 0.1% w/w to about 4% w/w.
In yet another embodiment, the present invention provides stable solid pharmaceutical composition comprising Azilsartan kamedoxomil and one or more pharmaceutically acceptable excipient(s), wherein pH adjusting agent include but not limited to fumaric acid and sodium hydroxide; wherein the ratio of fumaric acid and sodium hydroxide is about 1:0.2 to about 1:2, specifically about 1:0.4 to about 1:1; more specifically about 1:0.6 to about 1:0.7.
In another embodiment, the present invention provides stable solid pharmaceutical composition comprising Azilsartan kamedoxomil and one or more pharmaceutically acceptable excipient(s), wherein ratio of sodium hydroxide to crospovidone from extragranular material is in the range from about 1:1 to about 1:20.
In another embodiment, the present invention provides use of compound of formula I alone or in combination with compound of formula II for the treatment of hypertension in a subject in need thereof.
In another embodiment, the present invention provides stable solid pharmaceutical composition comprising Azilsartan kamedoxomil and one or more pharmaceutically acceptable excipient(s), wherein 1% w/v solution of acid and base combination results in pH above 5, specifically in the range from 5.1 to 7.0.
In another embodiment, the present invention provides stable solid pharmaceutical composition comprising Azilsartan kamedoxomil and one or more pharmaceutically acceptable excipient(s), wherein the composition further comprises use of one or more diuretics. In the context of the present invention, the pH of a solution or suspension is obtained by dissolving or suspending the pH adjusting agent in water at 25° C. to 40° C. at a concentration of about 0.1% w/v to 3% w/v is ≥5. Preferably the pH is of a solution or suspension obtained by dissolving or suspending the pH adjusting agent in water at a concentration of about 1% w/v to 3% w/v which is in the range from about 5.1 to about 7.0; wherein said composition provides stable dosage for oral administration. Specifically, the pH of a solution or suspension is obtained by dissolving or suspending the pH adjusting agent in water at 25° C. at a concentration of about 1% w/v to 3% w/v which is in the range from about 5.1 to about 7.0.
In another embodiment, the present invention provides stable solid pharmaceutical composition comprising combination of Azilsartan kamedoxomil and Chlorthalidone and one or more pharmaceutically acceptable excipient(s), wherein the composition can be administered orally for the treatment of lowering the blood pressure in a subject in need thereof.
In an embodiment, the present invention provides a method of stabilizing a compound of formula I or its salt optionally in combination with a diuretic as presented in compound of formula II, and a pH modifying agent. According to stabilizing method of the present invention, compound of formula I or its salt and optionally a diuretic in a solid preparation is significantly stabilized when the pH of a solution or suspension obtained by dissolving or suspending the pH adjusting agent in water at a concentration of about 0.1% w/v to 3% w/v is in the range from about 5.1 to about 7.0; wherein said composition provides stable dosage for oral administration. Specifically, the pH of a solution or suspension obtained by dissolving or suspending the pH adjusting agent in water at 25° C. at a concentration of about 1% w/v is in the range from about 5.1 to about 7.0.
In this context, 1% w/v solution or dispersion of acid and base combination are used in the composition, giving pH range from about 5.1 to about 7.0. When Azilsartan kamedoxomil and Chlorthalidone were granulated separately and dried, mixed together, lubricated, compressed into tablets and coated, the impurity levels of Azilsartan kamedoxomil were found to be low.
In another embodiment, the present invention is administered by oral route.
In another embodiment, the present composition provides stable solid dosage form, wherein the solid dosage form includes tablets, capsules, powder, pills, coated tablets, preferably tablets.
In a further embodiment, the present invention provides stable solid pharmaceutical composition comprising:
In another embodiment, the preferred diuretics in the present invention are thiazide diuretics like, Chlorothiazide, Chlorthalidone, Hydrochlorothiazide, Indapamide, Metolazone; preferred diuretic as per present invention is Chlorthalidone.
In another embodiment, the preferred diuretic in the present invention is Chlorthalidone.
In a further embodiment, the present invention provides stable solid pharmaceutical composition comprising:
In further embodiment, the present invention provides process for preparing a stable solid composition comprising:
In a further embodiment, the present invention provides a stable solid pharmaceutical composition comprising Azilsartan kamedoxomil; one or more pH adjusting agents and one or more pharmaceutically acceptable excipient(s) thereof; wherein the composition contains pH adjusting agent in 1% w/v solution of acid and base combination resulting in pH range from 5.1 to 7.0.
In further embodiment, the present composition provides use of fumaric acid (acid) and sodium hydroxide (base), which results in complete dissolution and detection of low level of impurities. Solution of about 1% w/v of acid and base combination is used in the composition, which gives pH range from about 5.1 to 7.0.
In a further embodiment, the present invention provides a process for preparation of stable solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s) thereof; optionally the composition comprises one or more diuretics.
In further embodiment, the present invention provides process for preparing solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s) thereof; wherein the process comprises the steps of:
In further embodiment, the present invention provides a process for preparing solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s) thereof in combination with a diuretic; wherein the process comprises the steps of:
In further embodiment, the present invention provides a process for preparing solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s) thereof in combination with a diuretic; wherein the process comprises the steps of:
In separate embodiments, the present invention provides a process for preparing stable pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s) thereof; wherein the process comprises steps of:
In another embodiment, the present invention provides a process for preparing stable pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s) thereof in combination with Chlorthalidone; wherein the process comprises steps of:
In separate embodiment, the present invention provides a method of treating a patient by administering a stable solid pharmaceutical composition comprising Azilsartan or its salt and one or more pharmaceutically acceptable excipient(s) thereof; optionally the composition comprising one or more diuretics; wherein the diuretic is Chlorthalidone.
Examples of the disintegrant include low substituted hydroxypropylcellulose, carmellose, carboxy-methyl-starch sodium, cross povidone, amino acid, starch, cornstarch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, carmellose sodium, carmellose calcium, croscarmellose sodium, hydroxypropylstarch, sodium carboxymethyl starch and the like.
Examples of the binders include povidone, dextrin, hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinyl alcohol, carboxymethylcellulose, pregelatinized starch, cellulose (e.g., microcrystalline cellulose), gelatin, starch, gum arabic powder, tragacanth, sodium alginate, pullulan, glycerol and powdered acacia.
Examples of the fillers or diluents include mannitol (eg. D-mannitol); white sugar (including purified white sugar); sorbitol (e.g., D-sorbitol), erythritol (e.g., D-erythritol), sucrose; sodium hydrogencarbonate; corn starch; potato starch; wheat starch; rice starch; partly alpha-sized starch; crystalline cellulose; light anhydrous silicic acid; precipitated calcium carbonate; calcium silicate; sodium hydrogen carbonate, calcium phosphate, calcium sulfate, calcium carbonate, precipitated calcium carbonate, calcium silicate and the like.
Examples of the lubricants include hardened oils, hydrogenated-castor oil, magnesium stearate, calcium stearate, glyceride behenate; sodium stearyl fumarate; stearic acid, talc (purified talc), sucrose esters of fatty acid, and the like.
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, polysorbate 20, polyoxyethylene(160); polyoxypropylene(30) glycol and the like.
Examples of the diuretic include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate, etc.), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide, etc.), antialdosterone preparations (e.g., spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (e.g., acetazolamide, etc.), chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like. In the present invention, preferable diuretic is thiazide diuretic, more specifically Chlorthalidone.
The above-mentioned composition preferably contains compound (I) (preferably (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-f{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]met-hyl}-1H-benzimidazole-7-carboxylate potassium salt); a pH adjusting agent (preferably fumaric acid and sodium hydroxide); a surfactant (preferably sodium lauryl sulphate); a diluent (preferably mannitol and crystalline cellulose); and a binder (preferably hydroxypropylcellulose).
Observation: The composition with fumaric acid (acid) and sodium hydroxide (base) exhibited low level of impurities and complete dissolution. 1% w/v solution/dispersion of acid and base combination used in the composition resulted in pH range from 5.1 to 7.0.
Manufacturing procedure of Example 06:
Manufacturing procedure of Example 07:
Based on the above data, it was observed that the compositions of present invention exhibited excellent stability at accelerated and long term stability conditions.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202021028444 | Jul 2020 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2021/055957 | 7/2/2021 | WO |
