MXPA99005664A - Pharmaceutical compositions for freeze drying - Google Patents

Abstract

A pharmaceutical composition comprising a nucleotide analogue, mannitol and a modifying additvewhich is sodium chloride or a polyol which is suitable for freeze drying.

Description

PHARMACEUTICAL COMPOSITIONS FOR LIOFILIZATION DESCRIPTION OF THE INVENTION The present invention provides a pharmaceutical composition suitable for lyophilization and a process for the preparation of the composition. Lyophilization is a well-known process used to prepare stable storage formulations of pharmaceutical compounds which otherwise undergo degradation when stored in the presence of water, for example due to disproportionation and / or hydrolysis. A typical lyophilization cycle consists of four stages. Freeze the composition of a compound to be lyophilized, a primary drying cycle which involves applying vacuum and sufficient heat to sublimate the ice present in the composition, and a second drying cycle which removes any residual water and then recovery of the lyophilized composition. It is an expensive process because it requires a long time and because low temperature and vacuum are required. A low temperature is needed because the vacuum needs to be applied at a temperature below the eutectic temperature for mixtures of crystalline substances or below the glass transition temperature or collapse for amorphous mixtures. This is to ensure that the water that is REF .: 30454 present evaporates without passing through liquid state and in this way the amorphous mixtures do not collapse. A collapsed amorphous mixture is effectively useless because it is very difficult to reconstitute and can be unstable. To keep costs low it is preferable that for collapse or eutectic temperature is not too low in order to reduce cooling costs. A higher collapse or eutectic temperature is also advantageous because evaporation is activated which reduces the period of time in which vacuum is needed. Suitable compositions for lyophilization have been sought which produce a stable product and for which the collapse or eutectic temperature is not too low. According to a first aspect of the invention, there is provided a pharmaceutical composition comprising a nucleotide analog, mannitol and a modifying additive which is sodium chloride or a polyol. The invention further provides a pharmaceutical composition in lyophilized form, spray dried or vacuum dried and in reconstituted form. According to the invention, there is further provided a process for the preparation of a composition according to the invention which comprises mixing the ingredients of the composition, and either freezing and drying the frozen mixture, or dispersing them (for example in hot air). ).

It has been found that the use of the combination of mannitol and the modifying additive in the compositions of the invention improves the long-term stability of the compositions after lyophilisation. Another advantage of using such a combination is that the rupture or fracture of the bottle during lyophilization is avoided. A nucleotide is a compound comprising a purine base or pyrimidine linked to a pento-sugar wherein one or more of the hydroxy groups of the pento-sugar are phosphorylated by a mono- or polyphosphite. A nucleotide analogue for use in the invention is generally a compound in which one or more of the three portions of which a nucleotide is constituted are modified, for example, by attachment of one or more substituents and / or substitution of one. or more structural atoms. The nucleotide used in the invention is preferably a nucleotide of WO 94/18216, ie, a compound of formula (I): wherein R 1 and R 2 independently represent hydrogen or halogen, R 3 and R 4 independently represent phenyl or C 1-6 alkyl optionally substituted by one or more substituents that are selected from OR 5, C 1 g alkylthio, NR 6 R 7, phenyl, COOR 8 and halogen, R 5 , R6, R7 and R8 independently represent hydrogen or C- ^ g alkyl, and X represents an acidic portion, or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) can exist in tautomeric, enantiomeric and diastereomeric forms, all of which are included within the scope of the definition. The pharmaceutically acceptable salts of the compounds of formula (I) include alkali metal salts, for example sodium and potassium salts; alkaline earth metal salts, for example calcium and magnesium salts; salts of group III elements, for example aluminum salts; and ammonium salts. Salts with suitable organic bases, for example salts with hydroxylamine; lower alkylamines, for example methylamine or ethylamine; with substituted lower alkylamines, for example hydroxy-substituted alkylamines; or with monocyclic nitrogen heterocyclic compounds, for example piperidine or morpholine; and salts with amino acids, for example with arginine, plant, etc., or an N-alkyl derivative thereof; or with an aminosugar, for example N-methyl-D-glucamine or glucosamine. Non-toxic physiologically acceptable salts are preferred, although other salts may also be useful, for example, to isolate or purify the product. Alkyl groups in the definitions of the compounds of formula (I) include linear, branched or cyclic, saturated or unsaturated alkyl groups. The aryl groups in the definitions of the compounds of formula (I) include both carbocyclic and heterocyclic groups. The groups may contain rings of various amounts of C atoms and may be fused ring structures. Particular carbocyclic aryl groups which may be mentioned are phenyl and naphthyl. Heteroaryl groups include nitrogen, oxygen or sulfur heterocycles and may contain one or more heteroatoms. Examples of heterocycles containing only one heteroatom include pyrrole, furan, thiophene and pyridine. Groups containing more than one heteroatom include pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole, etc. The halogen atoms which can represent R1 and R2 include F, Cl, Br and I. Preferably, R1 and R2 are the same, and most preferably represent Cl. Preferably, R3 and R4 represent C1-e alkyl optionally substituted by one or more substituents that are selected from OR5, C-6 alkylthio, NR6R7, phenyl, COOR8 and halogen. Halogens in which R3 and R4 may be substituted include Cl, Br and I, and especially F. Particularly preferred compounds are those in which R3 represents Cx_6 alkyl optionally substituted by alkylthio. Particular alkyl groups in which R3 may represent include propyl and butyl, and especially ethyl. Particular substituted alkyl groups in which R3 may represent include 2- (methylthio) ethyl.

Preferably, R4 represents Cx_6 alkyl optionally substituted by one or more, for example, three halogen atoms. Particular groups that R4 may represent include propyl and 3,3,3-trifluoropropyl. The acidic portions which X may represent include Bronsted-Lowry acids, ie, portions which act as proton donors. The acid portion may be mono- or poly-acid. Specific acidic portions which may be mentioned include -P (0) (0H) 2, -S03H and -C02H. Preferably X represents -P (O) (0H) 2. More preferably, the nucleotide analogue is N- [2- (methylthio) ethyl] -2- [(3,3,3-trifluoropropyl) thio] -5'-adenyl, monoanhydric acid with dichloromethylenebisphosphonic acid or a pharmaceutically salt acceptable thereof, that is, a compound of formula (la). (la) More preferably, the compounds of formula (la) are in the form of tetrasodium salt. The compounds of formula (I) can be prepared using the methods described in WO 94/18216. The compounds of formula (I) are useful because they show pharmacological activity in mammals. In a further aspect, the invention provides a composition as defined herein for use in therapy, in particular, in the prevention of platelet aggregation. Therefore, the compositions of the invention act as antithrombotic agents. In a further aspect, the invention provides a method for treating a platelet aggregation disorder, which method comprises treating a subject suffering from such disorder with a therapeutically effective amount of a pharmaceutical composition as defined herein. In a further aspect, the invention provides the use of a pharmaceutical composition as defined herein, in the manufacture of a medicament for treating a plague aggregation disorder. The additive or modifying agent preferably is a suitable polyol. This is because when NaCl is used as a modifying agent, the impurity profile is unfavorable. A polyol suitable for use in the invention is in general a straight chain polyhydric alcohol or a cyclic molecule comprising one or more keto or aldehyde groups, which preferably are a carbohydrate. The polyol used in the composition according to the invention preferably is sorbitol, lactose, sucrose, inositol or trehalose. More preferably, the modifying agent is sorbitol, because it has surprisingly been found that the long-term stability of lyophilized compositions comprising sorbitol is improved as compared to such compositions containing other modifying agents. The composition according to the invention preferably comprises mannitol as a crystallization agent. Suitably, the compositions of the invention comprise about 1% or more by weight of mannitol, for example 20-40%. However, there is a problem with mannitol, in that, at the time of lyophilization, the bottles containing the mixture without the modifying additive tend to fracture due to an amorphous to crystalline phase transition. The amount of modifying additive is preferably sufficient to prevent this phase transition from occurring, for example from about 3 to 25%. A suitable amount can be easily determined by conventional analytical techniques such as differential scanning calorimetry. However, the amount of modifying agent should not be too much in a way that causes the composition to collapse.

Preferably, the water content of the formulation is less than 5% by weight, more preferably less than 2% by weight, and much more preferably less than 1% by weight. The pharmaceutical composition according to the present invention optionally further comprises a pharmaceutically acceptable excipient, for example a chelating or sequestering agent, an antioxidant, an agent for adjusting the tonicity, a pH modifying agent and / or a buffering agent, example, one or more of those described in "Review of Excipient and pH's for Parental Products used in the United States" ("Review of excipients and pH for parenteral products used in the United States"). Yu-Chang John Wang and R. R. Kowal, J. Parenteral Drug Association, 34, 452-462 (1980). The process for preparing the pharmaceutical composition according to the present invention is suitably carried out using any lyophilization, vacuum drying or spray drying technique commonly used within the pharmaceutical area. In a further aspect, the invention provides a process for preparing a pharmaceutical composition as defined herein which comprises mixing a nucleotide analogue, mannitol and sodium chloride or a polyol modifying additive and subjecting the mixture to a lyophilization process, vacuum drying or spray drying. A preferred process according to the invention is a bottle lyophilization process. Such a process comprises filling sterile vials with a sterile filtered solution of the composition according to the invention. A plug for sterile lyophilization is partially inserted into the bottle which is to be frozen, for example at a temperature of -30 to 40 ° C, and subsequently freeze-dried in a frozen state. After drying, the plug is completely inserted before removing the bottle from the lyophilization unit. When to be used, but prior to administration, the pharmaceutical compositions according to the present invention are generally reconstituted in a pharmaceutically acceptable diluent. Examples of pharmaceutically acceptable diluents include water, saline and dextrose. Preferably water is used as the diluent. In a further aspect, the invention provides a process for preparing a pharmaceutical composition as defined herein, which comprises mixing a nucleotide analogue, mannitol and a sodium chloride or polyol modifying additive with a pharmaceutically acceptable diluent. Suitably, a solution of the pharmaceutical composition according to the invention obtained after reconstitution and containing mannitol, is an isotonic solution. In a preferred embodiment, the pH of the composition of the present invention is from about 6 to about 10, and more preferably from about 7 to about 9. The pharmaceutical composition according to the present invention, when reconstituted, is preferably administered by injection intravenously, subcutaneously or intramuscularly, preferably intravenously. The compositions according to the invention can be packaged in any suitably adapted pharmaceutical application device, for example syringes, bottles or ampoules, so that the addition of water allows the preparation in itself of an aqueous solution of the active ingredient in a form suitable for immediate administration to the patient. Such devices form a further aspect of the invention. The invention will now be described in more detail by the following examples.

Example 1 The freeze-dried compositions shown in Table 1 are prepared as follows. For each batch of aliquots of 5 ml of solution shown, they were filled into flasks and then placed in a Secofroid Lyolab G lyophilizer. They were frozen at -35 ° C. they were subjected to primary drying for 2 hours at -30 ° C, followed by 33 hours of primary drying during which the temperature gradually rose to 35 ° C and then 12 hours of secondary drying at 35 ° C. The vacuum was maintained at 100 mTorr during the primary and secondary drying.

Table 1 wherein the analog is a compound of formula (la). They are then stored under conditions shown in Table 2 and undergo the degradation that is shown by the amount of impurities.

Table 2 where the amount of impurities is a percentage in pesos and RH means relative humidity.

Example 2 The freeze-dried compositions included in Table 3 are prepared as follows. For each batch, 3 ml aliquots of the solution shown were filled into vials and then placed in a Virtis Genesis 25EL lyophilizer. They were frozen at -35 ° C, subjected to 2 hours of primary drying at -30 ° C, followed by 25-28 hours of primary drying at 5 ° C and then 11 hours of secondary drying at 35 ° C. Vacuum was maintained at 100 mTorr through primary and secondary drying.

Table 3 wherein the analog is a compound of formula (la).

After each batch was stored at 40 ° C and 75% relative humidity and presented the degradation shown in table 4.

Table 4 on the e to the m aurea is a% by weight and the impurity A is a compound of formula (Ib), which is and impurity B is a compound of formula (le) (le) where Q represents It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture or products to which it refers.

Claims (16)

CLAIMS ' Having described the invention as above, the content of the following claims is claimed as property:

1. A pharmaceutical composition comprising a nucleotide analog, mannitol and a modifying additive which is sodium chloride or a polyol.

2. The pharmaceutical composition according to claim 1, characterized in that the nucleotide is a compound of the formula wherein R1 and R2 independently represent hydrogen or halogen, R3 and R4 independently represent phenyl or C1_6 alkyl optionally substituted by one or more substituents which are selected from OR5, alkylthio from NR6R7, phenyl, COOR8 and halogen, R5, R6, R7 and R8 independently represent hydrogen or Cx_6 alkyl, and X represents an acidic portion, or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that R1 and R2 are halogen, R3 is C4 alkyl optionally substituted by C1_6 alkylthio, R4 is C1-6 alkyl optionally substituted by halogen, and X is -P (O) (OH) 2, -S03H or -C02H.

4. The pharmaceutical composition according to any of claims 1 to 3, characterized in that the nucleotide is N- [2- (methylthio) ethyl] -2- [(3,3,3-trifluoropropyl) thio] -5 'acid. -adenyl, monoanhydric with dichloromethylenebisphosphonic acid.

5. The pharmaceutical composition according to any of claims 1 to 4, characterized in that the modifying additive is a polyol.

6. The pharmaceutical composition according to any of claims 1 to 5, characterized in that the modifying additive is sorbitol.

7. The pharmaceutical composition according to any of claims 1 to 6, which further comprises 1% or more by weight of mannitol.

8. The pharmaceutical composition according to any of claims 1 to 7, characterized in that it is in freeze-dried, spray-dried or vacuum-dried form.

9. The pharmaceutical composition according to claim 8, characterized in that it is in reconstituted form.

10. The pharmaceutical composition according to any of claims 1 to 9, characterized in that it is at a pH of from about 6 to about 10. The pharmaceutical composition according to any of claims 1 to 10, characterized in that the content of Water is less than 5% by weight. 12. The pharmaceutical composition according to any of claims 1 to 11, characterized in that it is used in therapy. 13. A process for the preparation of a pharmaceutical composition, according to claim 8, which process is characterized in that it comprises mixing the ingredients of the composition, and either lyophilizing and drying them in a frozen mixture, or subjecting them to aspersion. 14. The use of a pharmaceutical composition, according to any of claims 1 to 11, characterized in that it is used in the manufacture of a medicament for the treatment of a platelet aggregation disorder. 15. A method to treat a platelet aggregation disorder, method. which comprises treating a subject suffering from such disorder with a therapeutically effective amount of a pharmaceutical composition according to any of claims 1 to

11. 16. A process for preparing a pharmaceutical composition according to any of claims 1 to 11, characterized in that it comprises mixing a nucleotide analogue, mannitol and sodium chloride or a polyol modifying additive, and subjecting the mixture to lyophilization, vacuum drying or a spray drying process. *