FIELD OF THE INVENTION

The present invention relates to Ivabradine hydrochloride premix comprising Ivabradine and process for preparing said premix. The present invention also relates to pharmaceutical compositions comprising said Ivabradine hydrochloride premix.

BACKGROUND OF THE INVENTION

Ivabradine hydrochloride of formula I  has very valuable pharmacological and therapeutic properties  and is useful in many cardiovascular diseases such as angina pectoris  myocardial infarct and associated rhythm disturbances and is chemically known as (S)-7 8-dimethoxy-3-{3-{N-[(4 5-dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amino)propyl)-l 3 4 5-tetrahydro-2H-3-benzazepin-2-one hydrochloride.

Ivabradine with a pharmaceutically acceptable acid have very valuable pharmacological and therapeutic properties  especially bradycardic properties  making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris  myocardial infarct and associated rhythm disturbances  and also in various pathologies involving rhythm disturbances  especially supraventricular rhythm disturbances  and in heart failure. Ivabradine hydrochloride is first disclosed in U.S. Patent No. 5 296 482.

The compound stability is one of the most important criteria by most of the regulatory agencies. Therefore one need to demonstrate that even after the formulation the stability of the compound or its respective form is intact over a period of shelf life. The compound transformations can occur also in the different solid state  because of changes in humidity or temperature or oxidative degradation conditions.

The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations  if the process conditions are not opportunistically controlled. Consequently  a stable Ivabradine hydrochloride would be a significant contribution to the art.

The solvent-based process uses organic solvents to dissolve and intimately disperse the drug and carrier molecules. Identification of a common solvent for both drug and carrier can be problematic  and complete solvent removal from the product can be a lengthy process. In addition  large volumes of solvents are generally required which can give rise to toxicological problems. The drug and carrier are typically dissolved in a solvent such as methylene chloride  acetone  ethanol and mixtures thereof and the solvent is later removed by precipitation techniques  evaporation or the like  while the drug/carrier solid premix is collected as a powdered mass.

In the case where there is difficulty with thermal instability and immiscibility between the drug and the carrier  the hybrid fusion-solvent method can be employed. The drug is first dissolved in a small quantity of organic solvent and added to the molten carrier. The solvent is then evaporated to generate a product that is subsequently milled to produce a powder. The pharmacokinetics  dissolution rates and processes for formulation of much different solid pharmaceutical dispersion is discussed at length in an article by Ford J.  in Pharm. Acta. Helv. 61  3; 69-88 (1986).

Premix or co-precipitation techniques employ the use of an organic solvent or solvents to dissolve drug and carrier molecules. Separation of the drug and carrier from the solvent on precipitation can rely on the solubility properties of either the drug or carrier. For example  Simonelli et al  Journal of Pharmaceutical Sciences  Vol. 58  No. 5  May 1969  describes a co-precipitation process wherein sulfathiazole is dissolved in sodium hydroxide  followed by addition of polyvinylpyrrolidone; hydrochloric acid is then added to effect co-precipitation. This process is based on co-precipitation employing the solubility of the drug at different pH values. Such reliance on the solubility of the drug may be problematic in that it is not generally applicable to ivabradine  as many such drugs do not exhibit a pH dependent solubility. Florence et al  Communications  J. Pharm. Pharmac.  1976  28 601  describes co-precipitation of trifluoperazine embonate and the polymers poly DL-aspartic acid and polymethylmethacrylate. The co-precipitates were prepared by dissolving the drug and polymer in dimethylformamide and adding the solution to a rapidly stirred volume of water. Both polymers and drug are insoluble in water.

Premixes are characterized by a variety of associated properties such as stability  flow  and solubility. Typical premixes represent a compromise of the above properties  as for example  an increase in stability and dissolution properties of the premix. Although there are a variety of premixes  there is a continual search in this field of art for premixes that exhibit an improved mix of properties. Thus  the instant invention provides a premix in which Ivabradine hydrochloride exists in stable crystalline form and process of manufacture of the premix and pharmaceutical compositions comprising said Ivabradine hydrochloride.

Moreover it is known from US7358240B2  US7384932B2 that the Ivabradine hydrochloride polymorphous forms d  dd can easily convert into one other forms depending on the possibility to acquire or to lose water. These transformations can occur also in the different solid state  because of changes in humidity and temperature conditions.

The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations  if the process conditions are not opportunistically controlled. Consequently  a stable crystalline Ivabradine hydrochloride would be a significant contribution to the art.

Though d  and dd crystalline form of Ivabradine hydrochloride and its process of manufacture have been described in Patent US7358240B2 and US7384932B2  Ivabradine hydrochloride in premix form  is an approach by the present inventors towards attaining a significantly more stable crystalline product having better dissolution properties that can be easily formulated to give pharmaceutical compositions.

During our research on Ivabradine hydrochloride polymorphous forms d  dd it was observed that this class of compounds is not stable during stability tastings. The Ivabradine hydrochloride has a tendency to change its polymorph and it appears that some different polymorph by-products are produced with time. The stability under nitrogen is known for Ivabradine hydrochloride from the European Pharmacopoeia and the US Pharmacopoeia. It was observed that these conditions are not sufficient for Ivabradine hydrochloride.

It was surprisingly found during the research that that the premix of Ivabradine hydrochloride polymorphous forms dd was more sable during the stability tastings than any other poly morph of the Ivabradine hydrochloride.

Therefore Ivabradine hydrochloride polymorphous forms dd in premix is an approach by the present inventors towards attaining a significantly more stable polymorph product having better dissolution properties that can be easily formulated to give pharmaceutical compositions.

OBJECT OF THE INVENTION:

Therefore  it is an object of the invention to provide a premix of Ivabradine hydrochloride and process for preparation of the said premix.

Another object of the invention is to provide pharmaceutical compositions comprising the aforementioned Ivabradine hydrochloride premix.

SUMMARY OF THE INVENTION:

In one of the aspect  of the present invention provides Ivabradine hydrochloride premix having enhanced stability and dissolution properties and process for preparation thereof.

In another aspect  of the present invention a process of preparing a premix comprising Ivabradine hydrochloride  and a pharmaceutically acceptable carrier or excipient  which process comprises:
(i) providing an intimate mixture comprising the solvent system  Ivabradine hydrochloride and pharmaceutically acceptable carrier or excipient  and optionally  water;
(ii) removing any water present from the mixture;
(iii) precipitating the premix of Ivabradine hydrochloride and the carrier or excipient.

In another aspect  the invention provides for pharmaceutical compositions comprising said Ivabradine hydrochloride premix.

Other features and advantages will be apparent from the specification which describes an embodiment of this invention.

DETAILED DESCRIPTION OF THE INVENTION:

The invention will now be described in details in connection with certain preferred and optional embodiments so that various aspects thereof may be more fully understood and appreciated.

In an embodiment  the present invention provides a premix of Ivabradine hydrochloride having enhanced stability  dissolution properties that can be easily formulated into pharmaceutical compositions. Ivabradine hydrochloride premix having enhanced stability and dissolution properties  according to the invention  wherein Ivabradine hydrochloride is stabilized by combining with suitable polymers/agents. Further  Ivabradine hydrochloride is present in stable crystalline form in the premix of Ivabradine hydrochloride.

According to present invention  the ratio of Ivabradine hydrochloride to pharmaceutical acceptable carrier or excipients is in a range of 1:1 to 50: 1.

The premix of the present invention is prepared by combining Ivabradine hydrochloride with suitable premixing agents in pharmaceutically acceptable proportions to yield desired characteristics of good stability and formulation properties.

Suitable carrier or excipients include pharmaceutically acceptable polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to croscarmellose Sodium  micro crystalline cellulose  hydroxyethylcellulose (HEC)  hydroxypropylcellulose (HPC)  hydroxypropylmethylcellulose (HPMC)  hydroxymethylethylcellulose (HEMC)  ethylcellulose (EC)  methylcellulose (MC)  cellulose esters  cellulose glycolate  hydroxypropyl methyl cellulose phthalate  polymethylacrylate (HPMCP)  Hypromellose  vinylpyrrolidone monomers but not limited to Polyvinylpyrrolidone and polyol but not limited to Mannitol. The said polymers/agents are used to facilitate the presence of a crystalline Ivabradine hydrochloride.

The solvent system used in the process for manufacturing of the premix may be selected from a group of organic  aqueous  hydroalcoholic solvents either alone or in combinations thereof. The said solvents are selected from toluene  acetone  Isopropyl alcohol  ethanol  methanol  methylene chloride  dimethylacetamide  dimethylsulphoxide  dimethylformamide  tetrahydrofuran and combinations thereof  and optionally  water. Generally toluene/water  tetrahydrofuran/water  or acetone/methanol mixtures are employed in a process according to the present invention.

In another embodiment  the present invention provides process for preparing the said Ivabradine hydrochloride premix by co-precipitation technique which alleviates the above described disadvantages associated with known techniques  and have also found that co-precipitation offers an advantageous preparation route for premix of Ivabradine hydrochloride.

There is therefore provided in a first aspect of the present invention a process of preparing a solid premix comprising Ivabradine hydrochloride thereof  and a pharmaceutically acceptable carrier or excipient  which process comprises:
(i) providing an intimate mixture comprising the solvent system  Ivabradine hydrochloride and pharmaceutically acceptable carrier or excipient  and optionally  water;
(ii) removing any water present from the mixture;
(iii) precipitating the premix of Ivabradine hydrochloride and the carrier or excipient.

As used herein  the term "intimate mixture" can denote a solution  suspension  emulsion  colloid  dispersion or the like. Generally  the term "intimate mixture" as used herein denotes a solution.

It is generally advantageous to first premix the carrier or excipient together with the solvent or solvents and optional water  and Ivabradine hydrochloride. Optionally  the carrier or excipient  Ivabradine hydrochloride and solvent can be subjected to heating sufficient to facilitate dissolving. Remove any water present from the mixture azeotropically. Cool the reaction mixture co-precipitating the Ivabradine hydrochloride and the carrier or excipient.

It is generally advantageous to first premix the Ivabradine hydrochloride together with the solvent or solvents and optional water  prior to addition carrier or excipient thereto. Subsequently  the carrier or excipient can be added to the initial intimate mixture contain Ivabradine hydrochloride. Optionally  the Ivabradine hydrochloride carrier or excipient and solvent system mixture can be subjected to heating sufficient to facilitate dissolving of the former in the latter.

The resultant premix can be separated from the remaining components  suitably by filtering or the like  and the co-precipitate washed to remove residual solvent  and dried. The co-precipitate can then be formulated in a suitable pharmaceutical form employing known formulatory techniques  substantially as hereinafter described.

There is further provided by the present invention a process of preparing a pharmaceutical composition comprising a solid premix substantially as hereinbefore described  which process comprises mixing a solid premix substantially as hereinbefore described together with a pharmaceutically acceptable carrier.

Conveniently the following combinations of carrier or excipient and co-precipitation medium can be employed in a process according to the present invention:

Example: 1.

Preparation of Ivabradine hydrochloride premix with Polyvinylpyrrolidone (PVP)

Charge methanol (750ml)  Ivabradine hydrochloride (100g) and Polyvinylpyrrolidone (37.5 gm) at 25-30oC to the flask under stirring  after completion of reaction distilled out methanol under vacuum up to 55 °C from the reaction mixture. Cool the reaction mixture to 25-30oC. Seed the reaction mixture with Ivabradine hydrochloride. Add acetone (1875 ml) to reaction mass in 1hr at 25-35°C. Stir the reaction mixture for 1-3 hours at 25-30oC and distilled out the solvent. Filter the product and dry and unload the product.

Dated this 15th day of December  2011


Dr. Alpesh Pathak
Applicant’s Agent