WO2019135691A1

WO2019135691A1 - A stable mono-layer solid dosage form containing combination of two active ingredients

Info

Publication number: WO2019135691A1
Application number: PCT/SA2018/050001
Authority: WO
Inventors: Hemant Kumar; Praveen Kumar; Arif Ansari; Ahmed JAMJOOM; Iftikhar AHSAN; Sheikh Shafiq
Original assignee: Jamjoom Pharmaceuticals Factory Company Limited
Priority date: 2018-01-04
Filing date: 2018-01-04
Publication date: 2019-07-11

Abstract

A monolayer solid dosage form comprising active agent(s) valsartan or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof wherein the composition exhibits bioequivalence to the commercially available bilayer tablet dosage form comprising valsartan and amlodipine besylate; when administered to human subject, under the bioequivalence parameters of a 90% Confidence Interval for AUC which is between 80% and 125%, and a 90% Confidence Interval for Cmax, which is between 80% and 125%.

Description

A stable mono-layer solid dosage form containing combination of two active ingredients. Field of the Invention

The present invention relates to mono layer solid dosage form comprising valsartan and amlodipine or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs or enantiomers and racemates thereof and a process of forming the same.

Background of the Invention

Angiotensin II is a very potent peptide hormone that causes the muscles surrounding the blood vessels to contract, which thereby significantly narrow the blood vessels. This narrowing increases the pressure within arterial vessels, causing high blood pressure (hypertension). Angiotensin receptor blockers (ARBs) are drugs that block the action of angiotensin II. As a result, arterial vessels dilate and blood pressure is reduced, thereby making it easier for the heart to pump blood. ARBs are therefore used to prevent heart failure as well as hypertension. Drugs in this class include candesartan (Atacand, Astra-Zeneca), eprosartan (Teveten, Solvay & Biovail), irbesartan (Avapro, BMS), losartan (Cozaar, Merck), olmesartan (Benicar, Medoxomil; Sankyo & Forest), telmisartan (Micardis, Boehringer Ingelheim), valsartan (Diovan, Novartis) and pratosartan (Kotobuki). ARBs are used alone or in combination with other classes of antihypertensive agents that include thiazide diuretics, b blockers, calcium channel blockers, rennin inhibitor, and ACE inhibitors, both for the treatment of hypertension and congestive heart failure.

Valsartan, a selective an angiotensin II receptor antagonist and is used in the treatment of cardiovascular disorders such as hypertension and heart failure. Valsartan is chemically described as N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl) [l,r-biphenyl]-4-yl]methyl]-L-valine.

PCT publication No. W0201700728 describes a pharmaceutical combination composition of valsartan with other classes of antihypertensive agents.

Chinese patent application No. CN105232551 discloses valsartan/amlodipine besylate compound preparation for treatment of cardiovascular disease.

PCT publication No. W02015/051771 discloses a stable pharmaceutical composition containing amlodipine and valsartan and method of making a mono-layer tablet.

U.S. Pat. No. 5,399,578 describes the preparation of valsartan and its pharmaceutically acceptable salt.

U.S. Pat. No. 4,879,303 discloses preparation of amlodipine and its pharmaceutically acceptable salt. The compound amlodipine (3-ethyl 5-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)- 1, 4-dihydro-6-methylpyridine-3, 5-dicarboxylate) is a potent and long acting calcium channel blocker having utility as an anti-ischemic and anti-hypertensive agent.

Chinese patent application No. CN 104367574 discloses a pharmaceutical compn. of amlodipine benzenesulfonate and valsartan. The pharmaceutical compn. is prepd. direct compression tabletting process.

Indian patent application No. IN2008MU00855A discloses a stable pharmaceutical composition containing amlodipine and valsartan.

U.S. Pat. Nos. 6,294,197, 6,485,745 and 6,858,228 discloses a solid oral dosage form of valsartan and optionally hydrochlorothiazide (HCTZ) by direct compression method having more than by weight based on total weight of the compressed solid oral dosage form, of the active ingredient.

U.S. Pat. No. 6,395,728 discloses combination of valsartan and amlodipine comprising from about 10 mg to about 200 mg of valsartan and 1 mg to about 180 mg amlodipine.

PCT publication no. WO 2007/022113 relates to monolayer and bilayer solid dosage forms of a combination of valsartan and amlodipine. This application discloses that for the 320 mg/5 mg fixed dose combination of valsartan and amlodipine it was not possible to get a bioequivalent product unless a bilayer tablet formulation was used.

EXFORGE^® is marketed brand for combination of amlodipine and valsartan. It is available in four different strengths: 5 mg/l60 mg; 10 mg/l60 mg; 5 mg/320 mg and 10 mg/320 mg.

It is a known fact that a bilayer tablet exhibit certain disadvantages. In particular, both layers are adhered to each other by compression. Thus, they may be separated relatively easily by improper handling and weight control of individual layers in a bilayer tablets is very difficult task. Further, during film-coating of bi-layer tablet, there are chances of layer separation. The bilayer tablets are usually made by wet granulation, which can be less economical, to form a granules. Specialized machines are required for producing such tablets. Moreover, the process of making bilayer tablets is less economical.

In light of this, it was desirable to prepare a mono layer dosage form of the said combination product, which would also be bioequivalent to the bilayer tablet. We have developed a novel mono layer pharmaceutical dosage form comprising amlodipine and valsartan or their pharmaceutically acceptable salts thereof, wherein the composition is bioequivalent to marketed product under the brand name of EXFORGE®. Summary of the Invention

The primary objective of the invention is to provide a mono layer pharmaceutical dosage form comprising active agent(s) (a)amlodipine or a pharmaceutically acceptable salts thereof and (b) valsartan or a pharmaceutically acceptable salts thereof wherein: (i) the composition exhibits bioequivalence to the commercially available bilayer tablet dosage form comprising amlodipine besylate and valsartan.

Another objective of the present invention is to provide a method of achieving bioequivalence between a mono layer pharmaceutical composition comprising active agent(s) (a) Amlodipine or a pharmaceutically acceptable salts thereof and (b) Valsartan or pharmaceutically acceptable salts thereof wherein: (i) the composition exhibits bioequivalence to the commercially available bilayer tablet dosage form comprising amlodipine besylate and valsartan.

Another objective of the present invention is to provide a method of achieving bioequivalence between a single layer pharmaceutical composition comprising active agent(s) (a)amlodipine or a pharmaceutically acceptable salts thereof and (b) valsartan or a pharmaceutically acceptable salts thereof wherein: (i) the composition exhibits bioequivalence to the commercially available bilayer tablet dosage form comprising amlodipine besylate and valsartan; when administered to human subject, under the bioequivalence parameters of: (a) a 90% Confidence Interval for AUC which is between 80% and 125%, and (b) a 90% Confidence Interval for Cmax, which is between 80% and 125%, and iii) valsartan is present in an amount greater than 250 mg.

Another objective of the present invention is to provide an easily-administrable combination compositions of valsartan and amlodipine, eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.

Another objective of the present invention is to provide a combinations and composition which have desired degree of uniformity in terms of its actives and excipient.

Yet another object of the present invention is to obtain an efficient and stable composition for use in the treatment of hypertension through the shelf life.

A further object of the present invention is to obtain a mono layer combination of valsartan and amlodipine with proper particle sizes which to allow both to manufacture and to achieve uniform mixing which is essential to achieve bioequivalent to bilayer marketed product. Detailed Description of the invention:

A novel pharmaceutical composition in the form of a mono-layer dosage form has been developed to carry out all objects, referred to above and to emerge from the following detailed disclosure.

The monolayer dosage form are prepared by dry granulation (compaction) of a mixture of amlodipine, valsartan and their pharmaceutically acceptable salts, hydrates, solvates or polymorphs or enantiomers and racemates thereof, followed by compression into tablets, which can be possibly coated. The monolayer dosage form is bioequivalent to the commercially available bilayer tablet dosage form comprising amlodipine besylate and valsartan.

EXFORGE^® is brand name for bilayer tablet dosage form available commercially comprising amlodipine besylate and valsartan”. The bilayer tablet strengths are 10 mg/320 gm and 5 mg/320 mg of amlodipine besylate and valsartan.

The term "amlodipine" as used herein includes free amlodipine base as well as its pharmaceutically acceptable salts with acids such as benzene sulfonic acid, acetic acid, phosphoric acid, sulphuric acid, tartaric acid, hydrochloric acid, citric acid, and the like. Especially preferred is the besylate salt.

The term "valsartan" as used herein includes valsartan acids its pharmaceutically acceptable salts such as valsartan sodium, valsartan potassium, valsartan calcium, valsartan magnesium and the like. The term "Amlodipine" and "valsartan" also include their isomers, enantiomers, stereoisomers solvates, hydrates, and the like. Valsartan and amlodipine may be used in the solid dosage forms in amounts effective to prevent or treat hypertension partly or completely. Amount of valsartan may vary from about 160 to about 640 mg, e.g. 320 mg, and that of amlodipine may vary from about 3 mg to about 30 mg

In an embodiment of the present invention the pharmaceutical composition comprises active agent(s) in an amount less than about 34% by weight, based on the total weight of the pharmaceutical composition.

In another embodiment of the present invention the pharmaceutical composition comprises valsartan in an amount less than about 34% by weight, based on the total weight of the pharmaceutical composition.

It has been found that the pharmaceutical composition of the present invention not only display the stable and robust formulation, but also display the improved characteristics associated even with dissolution. A person skilled in the art can easily determine the dose of the active agent(s) necessary to achieve the desired therapeutic effect and as practiced in prior art. The dose depends on the warm-blooded animal species, the age and the individual condition and on the manner of administration. In the normal case, an approximate daily dose in the case of oral administration for a patient weighing approximately 75 kg for oral application is of about 10 mg to about 320 mg, especially about 20 to about 120 mg, most preferably about 40 mg to about 80 mg for valsartan and about 1.0 mg to about 180 mg, preferably about 2.5 mg to about 50 mg, for the CCB, depending on the specific CCB. The exact dose of active agent(s) and the particular formulation to be administered depends on a number of factors, e.g. the condition to be treated, the desired duration of the treatment and the rate of release of the active agent. For example, the amount of the active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.

The present invention comprises a mono layer pharmaceutical dosage comprising of valsartan or a pharmaceutically acceptable salt thereof with a particle size d(50) is not less than 10 pm and d(90) is in range of 100 to l80pm and amlodipine or a pharmaceutically acceptable salt thereof with a particle size d(50) is not more than 30 pm and d(90) is not more than 60 pm and wherein the composition exhibits bioequivalence to the commercially available bilayer tablet dosage form comprising amlodipine besylate and valsartan.

The present invention comprises valsartan in the form of granules in an amount less than 34% by weight, based on the total weight of the pharmaceutical composition, amlodipine in the form of granules, in an amount of 0.5 to 4% by weight, a filler in an amount of 40 to 70% by weight, a glidant in an amount of 0.5 to 3% by weight, a disintegrant in an amount of 5 to 15% by weight and a lubricating agent in an amount of 0.5 to 2% by weight and wherein the composition exhibits bioequivalence to the commercially available bilayer tablet dosage form comprising amlodipine besylate and valsartan.

The combination therapy with valsartan and a calcium channel blocker results in a more effective antihypertensive therapy through improved efficacy as well as a greater responder rate.

The active may further comprises another active agent selected from the group comprising, but are not limited to, other calcium channel blocker (CCB), AT II Antagonist, renin inhibitors an angiotensin converting enzyme (ACE) inhibitor, an aldosterone synthase inhibitor an aldosterone antagonist, a dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP) inhibitor, an endothelin antagonist, alpha and beta adrenergic blockers, HMG CoA reductase inhibitors and a diuretic or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs or enantiomers and racemates thereof. “Pharmaceutical composition” includes powder, granules, pellets or those in unit dose forms such as tablets, capsules and the like; prepared by methods well known to a person skilled in the art. Thus, pharmaceutical preparations for oral use can be obtained by combining the active agent(s) with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable or pharmaceutically acceptable excipients to give tablets.

The term“mono layer” as per the invention includes solid oral dosage form wherein both the actives are present together either as coated or uncoated dosage forms preferably tablets. The coated or uncoated dosage forms can be prepared in various sizes and shapes as appreciated by the person skilled in the art. The above dosage forms can also made as mini tablets which can further be filled into capsule shells.

The term mono layer specifically excludes solid oral dosage forms wherein both the actives are present separately as bilayered tablets.

The pharmaceutically acceptable excipients or additives include but are not limited to disintegrants, binders, lubricants, glidants, fillers, diluents and the like.

The amounts of additive employed will depend upon how much active agent is to be used. One excipient can perform more than one function. The absolute amount of additives and the amounts relative to other additives are also dependent on the desired properties of the pharmaceutical composition and may also be chosen by the skilled artisan by routine experimentation without undue burden.

Disintegrants, include but are not limited to, cross linked polyvinylpyrrolidone (crospovidone, polyplasdone, kollidon XL); starches such as modified starches, pregelatinized starch, maize starch, pregelatinized starch, dried starch and sodium starch glycolate; gum such as alginic acid, sodium alginate, guar gum; croscarmellose sodium, cellulose products such as microcrystalline cellulose and its salts, microfine cellulose, low substituted hydroxypropylcellulose and mixtures thereof; ion exchange resins like polacrilin potassium; most preferably crossl inked polyvinylpyrrolidone, crospovidone, crosslinked carboxymethylcellulose.

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide and mixtures thereof. Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.

Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.

One or more of these additives can be selected and used by the skilled person having regard to the particular desired properties of the solid oral dosage form. The amount of each type of additive employed, e.g. glidant, binder, disintegrant, filler or diluent and lubricant may vary within ranges conventional in the art.

The pharmaceutical composition of the invention, wherein the core can be formed by various methods known in the art such as by dry granulation, wet granulation, direct compression, extrusion spheronization, layering and the like;

The pharmaceutical composition of the invention can be prepared for oral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of the pharmacologically active compound(s), alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for.

The invention provides in another of its objectives a process of making a pharmaceutical composition as hereinabove described. Such pharmaceutical compositions may be produced by working up components a) amlodipine b) valsartan and c) pharmaceutically acceptable additive(s) defined herein above in appropriate amounts, to form unit dosage forms.

In a preferred embodiment, there is provided a process of making a pharmaceutical composition as hereinabove described comprising the steps of i) blending the active agents with pharmaceutically acceptable additives, ii) subjecting the blend to slugging and roll compaction to form a compacted mass iii) sifting the compacted mass to form granules and iv) compressing the granules to form the solid oral dosage form. Compaction of the blend into compacted mass may be carried out using a slugging technique or preferably, roller compaction. The milling of the granules may be carried out according to conventional milling methods. The compression of granulates into tablet cores can be carried out in a conventional tabletting machine, eccentric tabletting machine or a rotary compression machine.

The tablets may further be coated by using any of the conventional coating techniques, such as pan or perforated pan, well known to the persons skilled in the art.

These coating layers comprise of one or more excipients selected from the group comprising coating agents, film forming polymer, plasticizer, opacifiers, colouring agents, antitacking agents and the like.

Coating agents which are useful in the coating process, include, but are not limited to, polysaccharides such as maltodextrin, alkyl celluloses such as methyl or ethyl cellulose, hydroxyalkylcelluloses (e.g. hydroxypropylcellulose or hydroxypropylmethylcelluloses); polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinylpyrrolidone and vinyl acetate (e.g. marketed under the brand name of Plasdone) and polymers based on methacrylic acid such as those marketed under the brand name of Eudragit. These may be applied from aqueous or non- aqueous systems or combinations of aqueous and non-aqueous systems as appropriate. Additives can be included along with the film formers to obtain satisfactory films. These additives can include plasticizers such as dibutyl phthalate, triethyl citrate, polyethylene glycol and the like, antitacking agents such as talc, stearic acid, magnesium stearate and colloidal silicon dioxide and the like, surfactants such as polysorbates and sodium lauryl sulphate and opacifying agents such as titanium dioxide and the like. All these excipients can be used at levels well known to the persons skilled in the art.

The protection scope of the present invention is set forth in the annexed claims and cannot be restricted to the illustrative disclosures given above, under the detailed description. Any alternative embodiments to be produced by those skilled in the art according to the basic principles, which are under the protection scope as set forth in the claims, shall be an infringement of the present invention.

EXAMPLES

Example 1 and 2 Amlodipine and Valsartan tablet composition

Brief Manufacturing Process

1) Valsartan, Amlodipine besylate, and a part of microcrystalline cellulose, colloidal silicon dioxide, and crospovidone were sifted together.

2) Magnesium stearate sifted through appropriate sieve and lubricated with blend of step 1. The blended material is compacted to form slugs/compacts.

3) The compacted mass is milled and sieved again to form granules. The remaining sifted portion of the microcrystalline cellulose, Crospovidone, colloidal silicon dioxide, are added and blended in a suitable blender.

4) The above prepared granules are lubricated with sifted magnesium stearate and compressed into the tablets.

5) The tablets are then coated using film coating composition.

Stability data for Valsartan and Amlodipine monolayer tablet of 320/10 mg Film Coated:

BDL*: Below Disregard limit

Bioequivalence Study

The test composition was prepared according to example 1 and was evaluated against EXFORGE® (amlodipine and valsartan) having 10 mg amlodipine besylate and 320 mg of Valsartan, by Novartis, as reference.

An open label, balanced, randomized, two treatment, two sequences, two-period, crossover oral bioequivalence study was carried out in 44 healthy human volunteers. Each received single dose of 10 mg of amlodipine besylate and 320 mg of valsartan in fasted state. 38 healthy volunteers received single dose of 10 mg of amlodipine besylate and 320 mg of valsartan in fasted state.

The study was monitored in terms of the AUC and C_max achieved with the test product and reference product. AUCs are areas under plasma concentration of valsartan— time curves or amlodipine-time curves. Generally, the values for AUC represent a number of values taken from all the subjects in a population and are, therefore, mean values averaged over the entire population. C_max, the observed maximum plasma concentration of valsartan or amlodipine is likewise an average value. The ratios of the log transformed mean values for C_max and AUC for the test and reference product (T/R ratio) is a measure of the bioequivalence between the test and reference product. Values between 80 and 125% for these intervals indicate bioequivalence as recommended by the SFDA Bioequivalence data for composition containing amlodipine and valsartan against the commercially available tablets EXFORGE^® (amlodipine and valsartan) is shown below in Tables 1 and 2.

Surprisingly, we have found that mono layered pharmaceutical dosage form comprising active agent(s) amlodipine besylate and valsartan exhibits bioequivalence to the commercially available bilayer tablet, EXFORGE^® (amlodipine and valsartan); when administered to human subject, under the bioequivalence parameters of: (a) a 90% Confidence Interval (Cl) for AUC which is between 80% and 125%, and (b) a 90% Confidence Interval for Cmax, which is between 80% and 125%.

TABLE 1

Fasted BE study data of Amlodipine against commercially available tablets Exforge ® (amlodipine and valsartan) N = 38

C_max = Maximum plasma concentration

AUC₍o-_t) = Area under the plasma concentration time curve from time 0 to t

TABLE 2

Fasted BE study data of Valsartan against commercially available tablets Exforge ® (amlodipine and valsartan) N = 38

C_max = Maximum plasma concentration

AUC₍o-_t) = Area under the plasma concentration time curve from time 0 to t AUC₍o-_¥) = Area under the plasma concentration time curve from time 0 to ¥

Claims

CLAIMS The invention claimed is:

1. A mono layer pharmaceutical dosage form comprising valsartan in the form of granules in an amount less than 34% by weight, based on the total weight of pharmaceutical composition, amlodipine in the form of granules, in an amount ranging from 0.5 to 4% by weight, a filler in an amount of 40 to 70% by weight, a glidant in an amount of 0.5 to 3% by weight, a disintegrant in an amount of 5 to 15% by weight and a lubricating agent in an amount of 0.5 to 2% by weight and wherein the composition exhibits bioequivalence to the commercially available bilayer tablet dosage form comprising amlodipine besylate and valsartan.

2. A mono layer pharmaceutical dosage form according to claim 1 , wherein valsartan is present in a unit dose in amount ranging from about 160 mg to about 640 mg.

3. A mono layer pharmaceutical dosage form according to claim 1, wherein the valsartan is selected from the group consisting of valsartan free base and pharmaceutically acceptable salts thereof.

4. A mono layer pharmaceutical dosage form according to claim 1 , wherein the amlodipine is selected from the group consisting of amlodipine free base and pharmaceutically acceptable salts thereof.

5. A mono layer pharmaceutical dosage comprising of valsartan or a pharmaceutically acceptable salt thereof with a particle size d(50) is not less than 10 pm and d(90) is in range of 100 to l80pm and amlodipine or a pharmaceutically acceptable salt thereof with a particle size d(50) is not more than 30 pm and d(90) is not more than 60 pm and wherein the composition exhibits bioequivalence to the commercially available bilayer tablet dosage form comprising amlodipine besylate and valsartan.

6. A mono layer pharmaceutical dosage form according to claim 1 , comprising pharmaceutically acceptable additives selected from the group comprising fillers or diluents, binders, lubricants, glidants, coloring agent and disintegrants

7. A mono layer pharmaceutical dosage form of claim 5 or 6, wherein the diluent is one or more selected from the group comprising confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactitol, fructose, mannitol, sucrose, starch, lactose, dibasic or tribasic calcium phosphate, calcium carbonate, calcium sulphate, xylitol, sorbitol, talc, micro-crystalline cellulose or mixtures thereof.

8. A mono layer pharmaceutical dosage form claim 5 or 6, wherein the lubricant is one or more selected from the group comprising Mg, Al, Zn or Ca stearate, polyethylene glycol, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, glyceryl behenate, talc and mixtures thereof.

9. A mono layer pharmaceutical dosage form of claim 5 or 6, wherein the glidant is one or more selected from the group comprising silicon dioxide, colloidal silica, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof.

10. A mono layer pharmaceutical dosage form of claim 5 or 6, wherein the disintegrant is one or more selected from the group comprising cross linked polyvinylpyrrolidone, maize starch, dried starch, pregelatinized starch, sodium starch glycolate, alginic acid, sodium alginate, guar gum, croscarmellose sodium, microcrystalline cellulose and its salts, microfine cellulose, low substituted hydroxypropylcellulose, ion exchange resins and mixtures thereof.

11. A mono layer pharmaceutical dosage form described in claim 1 or 5, which is in the form of tablets, capsules, granules, microparticles, minitablets and pellets.

12. A mono layer pharmaceutical dosage form of claim 1 or 5 is further coated.