WO2019239432A1

WO2019239432A1 - Trisodium sacubitril valsartan complex and hot-melt extruded pharmaceutical composition comprising thereof

Info

Publication number: WO2019239432A1
Application number: PCT/IN2019/050456
Authority: WO
Inventors: Nidhi BAGREE; Preeti Raut; Geena Malhotra; Manish Gopaldas Gangrade; Vaibhav Panditrao Deshmukh
Original assignee: Cipla Limited
Priority date: 2018-06-14
Filing date: 2019-06-14
Publication date: 2019-12-19

Abstract

The present invention relate to trisodium sacubitril valsartan complex with polymer as an extrudate and to a hot melt extruded pharmaceutical composition comprising, trisodium salt of valsartan sacubitril and at least one pharmaceutically acceptable polymer. A process for preparing a pharmaceutical composition comprising trisodium salt of valsartan sacubitril and at least one pharmaceutically acceptable polymer, comprises hot melt extrusion of the trisodium salt of valsartan sacubitril polymer blend to form extrudates and optionally mixing it with one or more pharmaceutically acceptable excipients.

Description

TRISODIUM SACUBITRIL VALSARTAN COMPLEX AND HOT-MELT EXTRUDED PHARMACEUTICAL COMPOSITION COMPRISING

THEREOF

FIELD OF THE INVENTION:

The present invention relates to trisodium sacubitril valsartan complex with polymer as an extrudate and to a hot-melt extruded pharmaceutical composition comprising trisodium sacubitril valsartan complex. The invention also relates to processes for the preparation of the said pharmaceutical composition and its use for the treatment and/or prevention of cardiovascular diseases.

BACKGROUND OF THE INVENTION:

Various factors are responsible or contribute to the efficacy of a drug. Amongst such factors solubility, bioavailability and lipophilicity are the three parameters that are closely interconnected. Lipophilic drugs have higher affinity to their respective target receptors and therefore the solubility increases which in turn results in the increment of its bioavailability. The drawback to this fundamental is that lipophilic drugs tend to have a higher molecular weight thus affecting their absorption and amounting to decreased solubility. So either the drug is more soluble and less lipophilic which in turn makes it less bioavailable or a drug can be more lipophilic and less soluble which also makes it less bioavailable which ultimately proves that there are very few cases where bioavailability can be increased. This principle applies to over 40% of present potential actives.

Trisodium sacubitril valsartan complex (code named LCZ696) is a combination drug consisting of two antihypertensive drugs (blood pressure lowering drugs), valsartan and sacubitril.

The combination is often described as a dual-acting compounds of angiotensin receptor blockers (ARB) and neutral endopeptidase inhibitors (NEPi). US 8,877,938 describes complex of trisodium valsartan-sacubitril hemipentahydrate in crystalline form.

Complex of trisodium valsartan-sacubitril is marketed under the trade name ENTRESTO by Novartis. The reduced formula of the complex of trisodium valsartan-sacubitril, as included in the ENTRESTRO product, is shown below as Compound-I as a single valsartan molecule with a single sacubitril molecule together with three sodium anions and 2.5 water molecules.

Compound I

Pharmaceutical solids can exist in different crystal forms such as crystalline, amorphous, or glass and also in solvated or hydrated states (Haleblian et al. , 1969,1975; Kuhnert-Brandstaetter, 1973; Sohn 2004). Polymorphism is the ability of any element or compound to crystallize as more than one distinct crystal species.

It is a well-known fact that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important physicochemical properties, such as melting point, chemical reactivity, vapor pressure, stability, solubility, dissolution rate, crystal habit, aqueous solubility, tableting behavior. Changes in certain of these physiochemical properties may ultimately affect the bioavailability of the drug. Also, after development of new crystalline form of a drug, preventing the conversion of developed crystalline form to another form during the storage of formulation and thus maintenance of new crystalline form is key requirement for the preparation.

Regulatory authorities desire to have all possible polymorphic forms of a new drug substance identified prior to approval of a product containing the drug. However, as is well known in the art, the existence of polymorphic forms of any given compound cannot be predicted, and there is no standard procedure for proceeding to make a previously unknown polymorphic form. Even after a polymorph has been identified, there is no possibility of predicting whether any additional forms will ever be discovered. This has been described in many recent articles, including A. Goho, Science News , Vol. 166, No. 8, pages 122-123 (August 2004).

Literature data show that the tri sodium sacubitril valsartan complex exists in different crystalline polymorphic forms.

The US8,877,938 patent characterizes the crystalline form of trisodium sacubitril valsartan complex by XRD peaks but does not provide the XRD figure of the compound.

CN105037289 A described crystalline Form II of a supramolecular complex of trisodium sacubitril valsartan complex.

WO2016049663 patent application publication claims three different crystal forms of complex of trisodium valsartan-sacubitril namely Form I, II and III. The forms are characterized by XRD, DSC and TGA.

WO20160125123 and W02017009784 claim amorphous form of complex of trisodium valsartan-sacubitril and methods for the preparation thereof, wherein the complex is first dissolved in a solvent. The process further requires the removal of the solvent to obtain amorphous form of the complex

W02017012917 claims amorphous complex of trisodium valsartan-sacubitril having water content of at maximum 4% by weight. This method also requires dissolving the complex in a solvent followed by either freeze drying or spray drying, to obtain the amorphous form.

WO20160151525 claims crystalline Form I of a supramolecular complex of trisodium sacubitril valsartan.

W020160201238 claims crystalline Form II of a supramolecular complex of trisodium sacubitril valsartan.

WO 2017/009784 claims crystalline Forms II, III and IV of trisodium salt of valsartan sacubitril complex

W02017042700 and WO2017037591 are other applications that gives the preparation of the amorphous form of the complex using solvent based process.

WO2017037596 and WO2017085573 are other applications that describe the preparation of amorphous solid dispersion of the complex.

Thus, although there are few prior art disclosures on crystalline forms of sacubitril- valsartan complex, formulations comprising the same and their process of preparation using solvents, may be undesirable as it may lead to an impure and unstable product with traces of hazardous solvents.

Thus, there exists a need to provide a composition comprising crystalline sacubitril valsartan complex which is stable, have improved aqueous solubility, improved dissolution profile, substantially and method of preparing such compositions which is simple, inexpensive, user friendly as well as commercially available and do not involve use of volatile organic solvents.

The inventors of the present invention during their continuous effort to provide compositions comprising trisodium sacubitril valsartan complex, developed a process, which involves hot melt extrusion technology to maintain a uniform distribution of excipients and the drug.

SUMMARY OF THE INVENTION:

The present invention provides Trisodium sacubitril valsartan complex with copolymers of PVP and vinylacetate (VA) ( KOLLIDON® VA64), wherein the said complex is an extrudate.

In one aspect, the present invention provides pharmaceutical composition comprising trisodium salt of valsartan sacubitril complex represented as compound (I) and at least one pharmaceutically acceptable polymer.

In an aspect, the composition is a hot melt extruded pharmaceutical composition.

In another aspect, composition comprises extrudate substantially in a crystalline form.

The substantially crystalline form of the present invention possesses certain physical and chemical properties which render them particularly suitable for pharmaceutical development, such as good solubility, permeability and bioavailability. In addition, they are suitable for bulk handling and formulation.

In yet another aspect, the invention provides a process for preparing stable pharmaceutical composition. The processes of the present invention afford an extrudate in a substantially crystalline form in high purity and high yield. Advantageously, they are environmentally friendly and suitable for use on a commercial scale.

In yet another aspect, the invention relates to the use of the hot melt extruded pharmaceutical composition for the treatment of hypertension or congestive heart failure.

According to another aspect of the present invention, there is provided a hot melt extruded pharmaceutical composition comprising an extrudate in a substantially crystalline form as described above, together with one or more pharmaceutically acceptable excipients.

According to another aspect of the present invention, there is provided an extrudate in a substantially crystalline form as described above for use in medicine.

According to another aspect of the present invention, there is provided an extrudate in a substantially crystalline form as described above for use in treating hypertension and heart failure.

According to another aspect of the present invention, there is provided the use of an extrudate in a substantially crystalline form as described above for use in the manufacture of a medicament for treating hypertension or heart failure.

According to another aspect of the present invention, there is provided a method of treating hypertension or heart failure comprising administering to a patient in need thereof a therapeutically effective amount of an extrudate in a substantially crystalline form as described above. BRIEF DESCRIPTION OF THE DRAWING:

Figure 1 is an X-ray powder diffraction spectrum of the composition of an extrudate of example 1.

Figure 2 is a comparative X- ray powder diffraction spectrum of the composition of example 2 between initial time point (top) and after 1 month storage (bottom).

Figure 3 and Figure 4 depict the comparative pharmacokinetics of RLD and Fl variant (tablets of example 2)

DETAILED DESCRIPTION:

Different crystalline forms of sacubitril-valsartan complex provide different advantages such as, for example stability of the form, stability of the formulation, and in pharmacokinetic profiles, wherein the process of preparation of the formulation also plays a major role.

The inventors of present invention have found that the solubility, bioavailability, stability of some crystalline form of sacubitril- valsartan complex was greatly improved when sacubitril valsartan complex was formulated using hot melt extrusion technology.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The term "extrudates" as used herein refers to solid product solutions, solid dispersions and glass solutions of trisodium sacubitril valsartan complex represented as compound (I) with one or more polymers and optionally pharmaceutically acceptable excipients. As used herein, the term "substantially the same X-ray powder diffraction pattern" is understood to mean that those X-ray powder diffraction patterns having diffraction peaks with 20 values within ± 0.2° of the diffraction pattern referred to herein are within the scope of the referred to diffraction pattern.

As used herein, the term "substantially pure" refers to trisodium salt of valsartan sacubitril complex having no greater than about 0.5% by weight of total impurities. Substantially pure trisodium salt of valsartan sacubitril complex forms another aspect of the present invention. Frequently, the trisodium salt of valsartan sacubitril complex of the invention will have no greater than about 0.2% by weight of total impurities. The impurity contents described herein relate only to the total of trisodium salt of valsartan sacubitril complex and related compound impurities, as determined by high performance liquid chromatography ("HPLC"), and any residual solvent impurities.

The present invention provides a pharmaceutical composition comprising trisodium salt of valsartan sacubitril complex represented as compound (I) and at least one pharmaceutically acceptable polymer.

In one aspect composition is a hot melt extruded pharmaceutical composition.

The term“sacubitril-valsartan complex" used in broad sense means trisodium (4- { [(2S,4R)-l(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl Jamino} -4- oxobutanoate )( (S)- 3-methyl-2-(N-{ [2'-(2H-l ,2,3,4-tetrazol-l-id-5-yl)biphenyl- 4-yl]methyl }pentanamido) butanoate) or sacubitril-valsartan trisodium including without limitation, its free form and its pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc. The pharmaceutically acceptable hydrates include, without limitation, base addition salts, including hemi-hydrates. Preferably, the trisodium sacubitril-valsartan hemipentahydrate form is used in the present invention.

According to one embodiment of the invention, the sacubitril- valsartan complex is present in an amount of about 1% to about 90% (w/w) based on the total weight of the composition. In a preferred embodiment, the Sacubitril Valsartan complex is present in an amount of about 10% to about 90% (w/w) based on the total weight of the pharmaceutical composition. According to one other embodiment of the invention, the Sacubitril Valsartan complex is present in an amount of about 20% to about 80 % (w/w), most preferably about 25% to about 75% (w/w) of the total formulation.

In yet another embodiment of the present invention, there is a pharmaceutical composition comprising the extrudate comprising the actives as sacubitril- valsartan complex with one or more polymers and optionally one or more pharmaceutically acceptable excipients prepared by hot melt extrusion process. In further preferred embodiment of the present invention, there is provided a pharmaceutical composition comprising the extrudate comprising the actives as sacubitril- valsartan complex with one or more polymers and optionally one or more pharmaceutically acceptable excipients prepared by hot melt extrusion process and further processing the extrudate to form the suitable dosage form.

Thus, the present invention encompasses an extruded article comprising sacubitril- valsartan complex. This extrudate typically comprises one or more pharmaceutically acceptable polymer in combination with the complex, wherein the complex is suitably homogeneously dispersed throughout the polymer. The extrudate may also further include one or more pharmaceutically acceptable excipients.

The melt-processible polymer of the present invention generally comprises about 5% to about 75%, more preferably about 10% to about 60% of the resulting extmdate, based on weight. Useful polymers thus include, without limitation, ionizable and nonionizable cellulosic polymers, including those having ether or ester or ether and ester substituents and copolymers thereof, including so-called “enteric” and“non-enteric” polymers; vinyl polymers and copolymers having hydroxy, alkylacyloxy, and cyclicamido substituents, including methacrylic acid copolymers and aminoalkyl methacrylate copolymers; various synthetic and naturally occurring polymeric ethers and esters of polyhydric alcohols; and mixtures thereof.

In one embodiment, the melt-processible polymer is an ionic or ionizable cellulosic polymer as described herein. In one embodiment, the melt-processible polymer is a nonionizable cellulosic polymer as described herein. In one embodiment, the melt processible polymer is a vinyl polymer as described herein. In one embodiment, the melt-processible polymer is a vinyl co-polymer as described herein. In one embodiment, the melt-processible polymer is a methacrylic acid co-polymer as described herein. In one embodiment, the melt- processible polymer is an aminoalkyl methacrylate copolymer as described herein. In one embodiment, the melt-processible polymer is a polymeric ether of a polyhydric alcohol as described herein. In one embodiment, the melt-processible polymer is a polymeric ester of a polyhydric alcohol as described herein.

Exemplary ionic cellulosic polymers include, without limitation, carboxymethylcellulose (CMC) and its sodium or calcium salts; carboxyethylcellulose (CEC); carboxymethylethylcellulose (CMEC); hydroxyethylmethylcellulose acetate phthalate; hydroxyethylmethylcellulose acetate succinate; hydroxypropylmethylcellulose phthalate(HPMCP); hydroxypropylmethylcellulose succinate; hydroxypropylcellulose acetate phthalate (HPCAP); hydroxypropylcellulose acetate succinate (HPCAS); hydroxypropyl methylcellulose acetate phthalate (HPMCAP); hydroxypropylmethylcellulose acetate succinate (HPMCAS); hydroxypropylmethylcellulose acetate trimellitate (HPM CAT); hydroxypropylcellulose butyrate phthalate; carboxymethylethylcellulose and its sodium salt; cellulose acetate phthalate (CAP); methylcellulose acetate phthalate; cellulose acetate trimellitate (CAT); cellulose acetate terephthalate; cellulose acetate isophthalate; cellulose propionate phthalate; cellulose propionate trimellitate; cellulose butyrate trimellitate; and mixtures thereof. Exemplary nonionic cellulosic polymers include, without limitation, methylcellulose (MC); ethyl cellulose (EC); hydroxyethyl cellulose (EEC); hydroxypropylcellulose (HPC); hydroxypropylmethylcellulose (HPMC); hydroxypropylmethylcellulose acetate; hydroxyethylmethylcellulose; hydroxyethylcellulose acetate; hydroxyethylethylcellulose; and mixtures thereof. Exemplary vinyl polymers and copolymers include, without limitation, methacrylic acid copolymers and aminoalkyl methacrylate copolymers, which are available, for example, from Rohm Pharma under the trade names EETDRAGIT® L, S, NE, RL, RS, and E. Other exemplary polymers include carboxylic acid functionalized polymethacrylates and amine-functionalized polymethacrylates; poly(vinyl acetal) diethylaminoacetate; polyvinyl alcohol (PVA); and polyvinyl alcohol/polyvinyl acetate (PVA/PVAc) copolymers; and mixtures thereof. Additional vinyl polymers and copolymers include, without limitation homopolymers of N- polyvinyl pyrrolidone (NVP), including, for example, Water-soluble polyvinylpyrrolidones (PVPs or povidones), such as KOLLIDON®l2 PF, 17 PF, 25, 30, and 90 F; water-soluble copolymers of PVP and vinylacetate (VA), such as KOLLIDON® VA64; and water-insoluble cross-linked polyvinylpyrrolidones (crospovidone), such as KOLLIDON® CL, CL-M, and SR, which are available from BASF; and mixtures thereof. Exemplary polymeric ethers and esters of polyhydric alcohols include, Without limitation, polyethylene glycol (PEG) and polypropylene glycol (PPG) homopolymers and copolymers (PEG/PPG); polyethylene/polyvinyl alcohol (PE/PVA) copolymers; dextrin; pullulan; acacia; tragacanth; sodium alginate; propylene glycol alginate; agar powder; gelatin; starch; processed starch; glucomannan; chitosan; and mixtures thereof. Other exemplary polymeric ethers include polyethylene oxides, polypropylene oxides, and polyoxyethylene-polyoxypropylene block copolymers (poloxamers) such as those available from BASF under the trade names LUTROL® F 68, F 127, and F 127-M; and mixtures thereof.

In an embodiment, the present invention discloses Trisodium sacubitril valsartan complex with copolymers of PVP and vinylacetate (VA) ( KOLLIDON® VA64), wherein the said complex is an extrudate.

In another embodiment, the pharmaceutical composition of present invention comprises copolymers of PVP and vinylacetate (KOLLIDON® VA64). In an embodiment of present invention, the composition comprises about 2% to about 80 wt % polymer, preferably about 10% to about 80% , most preferably about 10% to about 50% of polymer by weight.

Thus, the present invention provides a hot melt extruded pharmaceutical composition comprising trisodium salt of valsartan sacubitril complex, compound (I) and KOLLIDON® VA 64.

In an embodiment, ratio of amount of trisodium salt of valsartan sacubitril complex to the KOLLIDON® VA64 varies from 0.5: 10 to 10:0.5 by weight. Preferably, the ratio varies from 1 : 5 to 5: 1, more preferably the ratio varies from 1 :2 to 2: 1 by weight.

In another aspect hot melt extruded pharmaceutical composition comprises substantially pure crystalline extrudate of trisodium salt of valsartan sacubitril complex.

As polymorphic forms are reliably characterized by peak positions in the X-ray diffractogram, the substantial pure crystalline nature of extrudate has been analyzed, characterized and differentiated in more detail by powder X-ray diffraction spectroscopy which produces a fingerprint of the particular crystalline form. Measurements of 20 values are accurate to within ± 0.2 degrees. All the powder diffraction patterns were measured on a Rigaku Dmax 2200 advanced X- ray powder diffractometer with a copper-K-a radiation source.

The crystalline nature of an extrudate may be characterized by having an XRPD diffractogram comprising peaks at 6.47, 13.87 and 2l. l l°20 ± 0.2 °20. The XRD pattern may comprise further peaks at 17.41, 19.58, 23.87 and 28.05°20 ± 0.2 °20. The XRD pattern comprise still further peaks at 8.39, 9.61, 12.98, 16.01 and 26.16 °20 ± 0.2 °20

In an embodiment, crystalline form of an extrudate is characterized by having an XRPD spectrum as shown in Figure 1.

In an embodiment, the crystalline extrudate has an XRPD pattern with those peaks at °2Q values ± 0.2°2Q as depicted in Table 1. In an embodiment, the crystalline extrudate has substantially the same XRPD pattern with peaks at 2Q values as depicted in Table 1.

Table 1: Table of values for the XRPD pattern depicted in Figure 1

In addition to the complex and one or more polymer, the extrudate may further comprise additional excipients like plasticizers, disintegrants, flow regulators, lubricants, fillers, stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack. The composition may contain about 0.5% to about 10% alkalinizing agent by weight of the composition.

Plasticizers can be incorporated depending on the polymer and the process requirement. These, advantageously, when used in the hot melt extrusion process decrease the glass transition temperature of the polymer. Plasticizers also help in reducing the viscosity of the polymer melt and thereby allow for lower processing temperature and extruder torque during hot melt extrusion. Examples of suitable plasticizers which can be used in the present invention, include, but are not limited to, polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; citrate ester type plasticizers like triethyl citrate, citrate phthalate; propylene glycol; glycerin, low molecular weight polyethylene glycol; triacetin; dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate. The plasticizer is preferably present in an amount ranging from about 0% to about 10% by weight to the total weight of extrudate.

Suitable flow regulators are selected from highly dispersed silica (Aerosil), and animal or vegetable fats or waxes.

Various other additives may be used, for example dyes such as azo dyes, organic or inorganic pigments such as aluminium oxide or titanium dioxide, or dyes of natural origin; stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack. The extrudates can be in the form of beads, granulates, tube, strand or cylinder and this can be further processed into any desired shape.

The fraction of crystalline sacubitril- valsartan complex in the extrudate may range from about 5% to about 100%, but generally ranges from about 50% to about 100%, based on weight.

In another embodiment, the extrudate of crystalline sacubitril-valsartan complex is substantially free from residual solvents.

In another embodiment, the pharmaceutical composition comprising extrudate of crystalline sacubitril-valsartan complex is stable and does not convert to any other crystalline or amorphous form under stability conditions.

In another embodiment, the present invention is directed to pharmaceutical compositions comprising crystalline sacubitril-valsartan complex characterized by powder X-ray diffraction (PXRD).

In an embodiment of present invention, the extrudate is cut into pieces after solidification and can be further processed into suitable dosage forms. More preferably the extrudates thus finally obtained from the above process are then milled and ground to granules or other solid forms by the means known to a person skilled in the art.

According to another aspect of the present invention, there is provided a process for preparing hot melt extruded pharmaceutical composition comprising trisodium salt of valsartan sacubitril complex, compound (I) and KOLLIDON® VA64, wherein extrudate is in the crystalline form. The melt extrusion process involves preparation of extrudates and is carried out in hot melt extrusion equipment. The parameters of the hot melt extrusion process such as temperature, screw configuration, use of vacuum, screw rpm, feed rate, zone temperatures, die temperatures, melt temperature, chiller temperature, chill roll speed and such other parameters play a critical role in order to achieve the end product in the form of a solid dispersion with all desirable dosage form and stability characteristics.

In an embodiment, Sacubitril and Valsartan may be prepared by any known processes. Further, trisodium sacubitril valsartan complex may be prepared by any known processes.

The trisodium sacubitril valsartan may be in any crystalline or amorphous form, solvated form or in a mixture of any polymorphic forms.

The present invention also provides a process to manufacture the extrudates and further processing the extrudates into suitable dosage forms.

Typically, the melt-extrusion process comprises the steps of preparing a homogeneous melt of one or more drugs and the polymer, and cooling the melt until it solidifies.“Melting” means a transition into a liquid or rubbery state in which it is possible for one component to get embedded homogeneously in the other. Melting usually involves heating above the softening point of the polymer. In an embodiment, hot melt extrusion process of present invention to prepare extrudates involves forming a powder blend of complex and polymer and optionally one or more suitable excipients, transferring the blend through a heated barrel of the extruder, whereby the powder blend melts and molten solution product is collected on a conveyor whereby it is allowed to cool and form an extrudate.

The process of hot melt extrusion is carried out in the conventional extruders as known to a

person skilled in the art. Suitable extruders include single screw extaiders, intermeshing screw extruders or else multi screw extruders, preferably twin screw extruders, which can be co rotating or counter rotating and, optionally, be equipped with kneading disks. It wall be appreciated that the working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder and the type of polymer that is used. The screws of a twin screw-extruder usually provide different types of mixing and conveying conditions at various zones in the barrel. Higher mixing elements leads to more uniform mixing, higher shear and more residence time to the material. While the less mixing element or low angle in mixing element leads to less mixing, less shear and less residence time. During product development of the present invention, various modular screws with multiple elements fitted on a common shaft, allowing the tailoring and optimization of the screw design were experimented. The length of the screw in relation to the barrel diameter (the L/D ratio) is chosen to optimize the degree of mixing and the number of zones required to achieve the final product char acteristics.

The constant feeding rate and screw speed throughout the process is important as the combination of these two factors establishes the level of fill in extruder. This is critical to the process, because it governs the balance between the weak and strong mass transfer mode. Due to constant feed rate and screw speed, there will be a constant amount of material in the extruder and thus the shear stress and residence time applied to material remains constant. The inventors of present invention after various experiments have optimized the dimensions and process parameters to achieve the desired crystalline form of complex with desired properties. Preferably, the screw configuration for the composition of present invention was set to provide higher residence time and shear to the drug-polymer mix, in the barrel. in an embodiment of present invention, the melt temperature used during the process of hot melt extrusion is in the range from about 70°C to about 20Q°C. In a preferred embodiment, the melt temperature used during the process of hot melt extrusion is in the range from about 80° C to about 180°C

The extrudates can be in the form of beads, granulates, tubes, strands or cylinders and these can be further processed into any desired shape.

The processing conditions involved in making the extrudates, help in uniform distribution of the drugs throughout the blend and also improve the bioavailability.

During the operating process of melt extruder, the setting of zone temperature plays an important role as it affects the product stability and dissolution. An improper setting of zone temperature has certain disadvantages such as:

1. Setting of high temperatures in the starting zones will lead to partial melting of the active blend that will lead to the formation of hard lumps.

2. Improper melting of the active blend due to low temperature in the hot melt extruder, will lead to extrudes with unmelted drugs.

3. Setting of high temperatures in the zones will lead to the decomposition of drugs.

The zone temperature of the melt extruder is preset to a gradual increase in temperature ranging from about l°C to about 250°C. Most preferably, the melting occurs at the temperature ranging from about 50°C to 250°C.

In an embodiment, tri sodium sacubitril valsartan complex and the polymer are mixed and then fed continuously to a temperature controlled extruder causing the complex to be molecularly dispersed in the molten polymer. The resulting extrudate is cooled to room temperature and milled into a fine powder. This process also helps in maintaining less temperature in the extruder, which ultimately helps in reduction of hard lumps and also prevents the drug from decomposition.

The currently available tablet dosage form is formulated using hot melt extrusion (Meltrex) technology, which helps in increasing the bioavailability by dispersing the active ingredient in molecular level. Moreover, this technology is advantageous over conventional technologies by suspending the drug particles to deaggregate in the polymer melt due to intense mixing and agitation and also by allowing high drug loading.

The pharmaceutical compositions of the present invention comprising sacubitril- valsartan complex can be administered to a subject via any conventional means including, but not limited to, orally, rectally, ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracistemally, intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or as a buccal or nasal spray. According to embodiment of present invention, the pharmaceutical composition of present invention is administered orally.

Moreover, the extrudates/granules of crystalline sacubitril- valsartan complex according to the present invention may be formulated into any suitable dosage form, such as but not limited to, unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution, transdermal patches and sprinkles, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like. Liquid or semisolid dosage form (liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, patches, spot-on), injection preparations, parenteral, topical, inhalations, buccal, nasal etc. may also be envisaged under the ambit of the invention.

According to embodiment of present invention, the pharmaceutical composition of present invention is a solid dosage form. Solid dosage forms according to the present invention are preferably in the form of tablets which may be coated or extrudates of the complex are filled in capsules but there also are other conventional dosages such as powders, pellets, capsules, suspensions, solutions, dry syrups, emulsions and sachets that may be provided. One or more optional pharmaceutically acceptable excipients required for the preparation of suitable dosage form may include, but are not limited to, bulking agents/ diluents, binders, disintegrating agents, lubricants, glidants, coloring agents, alkalinizing agents, plasticizers, chelating agents and coating agents.

Suitable bulking agents/diluents according to present invention, may include one or more of, but not limited to, dibasic calcium phosphate, calcium Sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, maltodextrin, dextrose excipients, croscarmellose sodium, isomalt, PVA, saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, maltose, fructose, lactitol, lactose, mannitol, Sorbitol, starch, starch pregelatinized, sucrose, Sugar compressible, Sugar confectioners and mixtures thereof. The diluent may be present in a quantity from about 30% to about 85% by weight of the composition.

Suitable binders may include one or more of, but not limited, to methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyvinyl alcohol, pullulan, Starch, pregelatinized Starch, agar, tragacanth, sodium alginate, propylene glycol, alginate and other cellulose derivatives and equivalents thereof. Preferably the binder is present in a quantity from about 1% to about 15% by weight of composition.

Suitable disintegrants may include one or more of but not limited, to starches, clays, celluloses, algins, gums or crosslinked polymers one or more of low substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, Sodium starch glycolate, crospovidone, croscarmellose Sodium, starch, crystalline cellulose, hydroxypropyl starch, Polacrillin potassium and partially pregelatinized starch. The disintegrant may be presenting quantity ranging from about 1% to about 10% by weight of the composition.

Suitable lubricants/glidants may include one or more of, but not limited to, Stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil. Sucrose esters of fatty acid, PEG microcrystalline wax, colloidal silicon dioxide and equivalents thereof. Optionally, the formulation may incorporate one or more of the above lubricants or glidants. The glidant and lubricant may each be present in an amount from about 0.5% to about 5% by weight of the composition. Suitable coloring agents may be added.

The composition may further comprise alkalinizing agents including, but not limited to, calcium carbonate, calcium phosphate, magnesium carbonate, magnesium oxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, Sodium hydrogen carbonate and equivalents thereof. The formulation may incorporate one or more of the above alkalinizing agents.

Plasticizers which may be used in the pharmaceutical composition of the present invention, include, but are not limited to proplylene glycol, polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; citrate ester type plasticizers like triethyl citrate, citrate phthalate; propylene glycol; glycerin; polyethylene glycol (low & high molecular weight); triacetin; dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate, glycerol palmitosterate and mixtures thereof. According to the present invention, plasticizers may be present in an amount of from about 5 % to about 20 % w/w of total formulation.

Suitable chelating agents include, one or more of, but not limited to ethylenediaminetetraacetic acid (EDTA), disodium EDTA and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and derivatives thereof.

The pharmaceutical composition, according to the present invention, may be seal coated. Preferably, the tablet may be seal coated and finally film coated or the tablet may be seal coated and further enteric coated.

According to an embodiment of the present invention, pharmaceutical composition may be film coated with Ready colour mix systems (such as Opadry colour mix systems). According to the present invention, film coating polymer may be present in an amount from about 2% to about 10 % w/w of total formulation.

The suitable dosage form from the extrudates and optionally one or more pharmaceutically acceptable excipients can be prepared by the conventional processes known in the art such as such as direct compression, wet granulation, fluidized bed granulation, extrusion, solvent evaporation and are not intended to limit the scope of the invention to form the desired dosage form.

According to a preferred embodiment, the extrudates as obtained above may be mixed, sieved, sifted and compressed into a single tablet or may be filled into capsules or sachets or the extrudates in the form of granules may be administered directly. Alternatively, the tablet may be seal coated and finally film coated. Accordingly, the pharmaceutical composition of present invention comprises an extrudate comprising crystalline sacubitril- valsartan complex in combination with one or more polymer, optionally one or more pharmaceutically acceptable excipients and one or more pharmaceutically acceptable excipients.

Trisodium sacubitril valsartan complex has been found to be effective for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction. Pharmaceutical compositions according to the present invention comprise crystalline form of trisodium sacubitril valsartan complex as an active ingredient together with one or more pharmaceutically acceptable carriers, excipients or diluents. Any conventional technique may be used for the preparation of pharmaceutical compositions according to the invention.

Suitably, the pharmaceutical composition is in the form of a solid dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions.

Pharmaceutical compositions according to the present invention may preferably comprise 24 mg sacubitril and 26 mg valsartan, 49 mg sacubitril and 51 mg valsartan, or 97 mg sacubitril and 103 mg valsartan along with a pharmaceutically acceptable carrier.

In another embodiment, the pharmaceutical solid formulation for treatment of a disease or disorder selected from the group consisting of hypertension, heart failure, congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction, atherosclerosis, angina, renal insufficiency, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, and renal failure conditions

The invention is further described by reference to the following examples, which set forth in detail certain aspects and embodiments of the preparation of compounds and compositions of the present invention. It will be apparent to those skilled in the art, that many modifications, both to materials and methods, can be practiced without departing from the purpose and intent of this invention. The examples that follow are not intended to limit the scope of the invention as described herein above or as claimed below.

EXAMPLES

Example 1: Preparation of extrudates

i. Sacubitril Valsartan Trisodium Hemi-pentahydrate (227.01 mg) and KOLLIDON® VA64 (113.51 mg) were sifted and blended using rapid mixer granulator for about 30 minutes.

ii. the material obtained in step (i) was loaded to a hot melt extruder to get extrudates.

The XRD of the solid molecular complexes were evaluated and presented in Fig. 1.

Example 2: Preparation of Sacubitril and Valsartan tablets 97/103 mg Table 2:

i. Sacubitril Valsartan Trisodium Hemi-pentahydrate (227.01 mg) and Kollidon VA64 (113.51 mg) were sifted and blended using rapid mixer granulator for about 30 minutes.

iii. The extrudates obtained in step (ii) were further milled and blended with the Microcrystalline Cellulose, Crospovidone, Colloidal silicon dioxide and Hydroxypropyl Cellulose and further lubricated with magnesium stearate.

iv. Compressed the blend of step (iii) to form tablet.

v. Prepared the film coating solution and coated tablets to obtain film-coated tablets.

The XRD of the solid molecular complexes were evaluated Example 3:

It was observed that when sacubitril- valsartan complex was processed using hot-melt extrusion with the preferred parameters then the final formulation that was obtained contained the crystalline extrudate and this form did not got converted to any other crystalline or amorphous form during the storage for 1 month.

FIG. 2 indicates comparative X-ray powder diffractogram (XRD) of an extrudate at initial time point (top) and after 1 month storage of the tablets (bottom) as per the example 2 above.

Example 4:

Evaluation of comparative pharmacokinetics of RLD and Fl variant (tablets of example 2) following a single oral route of administration in male SD rats. The studies indicate higher Cmax as compared to RLD.

Table 3:

Further, Fig 3 depicts Valsartan mean concentrations (ng/ml). Table 4 shows the Valsartan PK parameters.

Table 4

Table 5:

Claims

We Claim;

1. Trisodium sacubitril valsartan complex with copolymers of PVP and vinylacetate (VA), wherein the complex is an extrudate.

2. The extrudate according to claim 1, characterized by having an XRPD diffractogram comprising peaks at about 6.47, 13.87 and 21.11°2Q ± 0.2 °2Q.

3. The extrudate according to claim 2, characterized by having an XRPD diffractogram comprising further peaks at 17.41, 19.58, 23.87 and 28.05°20 ± 0.2 °2Q.

4. The extrudate according to claim 3, characterized by having an XRPD diffractogram comprising further peaks at 8.39, 9.61, 12.98, 16.01 and 26.16 °20 ± 0.2 °20

5. The extrudate according to any one of claims 1 to 4, characterized by having an XRPD spectrum as shown in Figure 1.

6. The extrudate according to any one of claims 1 to 5, wherein at least 98% of complex is in the crystalline form.

7. The extrudate according to claim 1, wherein the ratio of amount of trisodium salt of valsartan sacubitril complex to the copolymers of PVP and vinylacetate (VA) varies from 0.5: 10 to 10:0.5 by weight; preferably, the ratio varies from 1 :5 to 5: 1; more preferably the ratio varies from 1 :2 to 2: 1 by weight.

8. A pharmaceutical composition comprising trisodium salt of valsartan sacubitril complex represented as compound (I)

and at least one pharmaceutically acceptable polymer, wherein composition is hot melt

extruded pharmaceutical composition.

9. The pharmaceutical composition according to claim 8, wherein pharmaceutically acceptable polymer is selected from ionizable and nonionizable cellulosic polymers, including those having ether or ester or ether and ester substituents and copolymers thereof; enteric and non-enteric polymers; vinyl polymers and copolymers having hydroxy, alkylacyloxy, and cyclicamido substituents, including methacrylic acid copolymers and aminoalkyl methacrylate copolymers; synthetic and naturally occurring polymeric ethers and esters of polyhydric alcohols; and mixtures thereof.

10. The pharmaceutical composition according to claim 9, wherein pharmaceutically acceptable polymer is vinyl polymers and copolymers, preferably water-soluble copolymers of PVP and vinylacetate (VA).

11. The pharmaceutical composition according to claim 10, wherein composition comprises about 2% to about 80 wt % polymer, preferably about 10% to about 80% , most preferably about 10% to about 50% of polymer by weight.

12. The pharmaceutical composition according to claim 11, wherein the ratio of amount of trisodium salt of valsartan sacubitril complex to the copolymers of PVP and vinylacetate (VA) varies from 0.5: 10 to 10: 0.5 by weight; preferably, the ratio varies from 1 : 5 to 5: 1; more preferably the ratio varies from 1 :2 to 2: 1 by weight.

13. The process for preparing a pharmaceutical composition according to any one of claims 8 to 12, wherein the process comprises hot melt extrusion of the compound (I) polymer blend to form extrudates and optionally mixing it with one or more pharmaceutically acceptable excipients.

14. The process according to claim 13, wherein the process comprises preparing a homogeneous melt of the compound (I), at least one polymer and optionally one or more pharmaceutically acceptable excipients, extruding the melt and cooling the melt until it solidifies.

15. The process according to claim 14, wherein the melt is formed at a temperature ranging from about 70°C to 200°C.

16. The process according to any one of claims 13 to 15, wherein the compound (I), at least one polymer and optionally, one or more pharmaceutically acceptable excipients are processed to form a powder blend which melts on passage through the heated barrel of an extruder, to form a molten solution product and subsequently cooled to form an extrudate.

17. The process according to any one of claims 13 to 16, wherein the process further comprises forming the extrudates as beads, granulates, tubes, strands and/or cylinders.

18. The pharmaceutical composition according to any one of claims 8 to 17, for use in treatment of a disease or disorder selected from the group consisting of hypertension, heart failure, congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction, atherosclerosis, angina, renal insufficiency, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, and renal failure conditions.

19. Use of a pharmaceutical composition according to any one of claims 8 to 17 in the manufacture of a medicament for the treatment of hypertension, heart failure, congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction, atherosclerosis, angina, renal insufficiency, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, and renal failure conditions.