The lyophilisate with improved recoverability in the initial state (options), method thereof and pharmaceutical drug

 

(57) Abstract:

The invention relates to lyophilizate with increased dissolution rate, which can be restored without the formation of particles, which is achieved by re-heating of selected solutions in bottles to a temperature of from 30 to S directly in the freeze-dryer for 10 minutes before 4 o'clock the Proposed lyophilizate substances selected from the group methanesulfonate 2-methyl-5-methylsulphonyl-4-(1-pyrrolyl)benzoylpyridine, hydrochloride N-[2-methyl-4,5-bis(methylsulphonyl)benzoyl]guanidine or the methanesulfonate of 4-isopropyl-3-methylsulfonylbenzoyl, and pharmaceutical preparation containing these lyophilizate. The invention allows to obtain products without the formation of particles with a high dissolution rate. 6 C. and 3 h.p. f-crystals.

The invention relates to lyophilizates, characterized by an increased dissolution rate and improved recoverability, as well as the way they are received.

Lyophilization, also known as freeze-drying, is a long-established method widely used for the preservation of certain substances in mild conditions, for example, canning thermosensitive pexeva substance dried frozen then they can be very easily restored to the original state, which is enough to add water or any other solvent. At this first stage, as a rule, consists in freezing the original materials at temperatures up to-70C. After that, the process of drying by sublimation of them remove the water that is in sealed containers (liophilization) in high vacuum, obtaining dried by sublimation of a substance.

The method of freeze-drying is used, in particular, for conservation of sensitive drugs as the role of this method when it comes to drugs, it is difficult to overestimate. In particular, it concerns the safety of their properties during storage, i.e., to eliminate the risk of changes, rearrangements or even destruction of their structure, which could lead to a significant decrease their effectiveness.

When the freeze-drying process, special attention is constantly paid to the accumulation of more and more active component in the smallest possible volume. In this regard, often used concentration close to the saturation concentration of the active component. This is necessary from the point of view of efficiency of technological processes.

However, in the build without the formation of particles, that eliminates the possibility of parenteral use. This is due to the presence of crystals formed by cooling after exceeding the ratio of dissolution saturation. The rate of dissolution of crystals is considerably inferior to that of molecules in amorphous form.

Thus, the purpose of this invention was to develop a method of producing liofilizatow, which would have increased the dissolution rate, and when you restore them, even if their concentration was close to that of saturation, it would be possible to avoid the formation of particles. Unexpectedly it was found that lyophilizate with the desired improved properties can be obtained if the solution prepared for use in the process of freeze-drying, heat directly in the freeze-dryer and quickly cooled to the freezing temperature.

Thus, the present invention relates to a method of producing liofilizatow with increased dissolution rate, characterized in that the appropriate, pre-selected for lyophilization solutions, the selection of which, if necessary, preceded by heating in order to accelerate the dissolution of the substance and filtering (neobyzantine dryer, then quickly hold phase freeze until the desired low temperature freeze-drying.

Property "quickly" in this context means the period from 10 min to 4 h, preferably from 30 minutes to 2 hours, most preferably from 30 min to 1 h the temperature of the freeze-drying can be down to-70C. In the preferred embodiment, using a temperature of about-50C.

In conventional freeze-drying substance or active component is heated in order to accelerate the dissolution. During sterilization, the usual in the case of drugs, the dissolution is followed by stage sterilization by filtration and selection. These two stages, depending on the batch size of the product can take several hours. This solution automatically cooled to room temperature. Thus, the freeze-dryer is loaded at room temperature, after which the speed limit are phase freezing (from room temperature to about-50C). This is followed by a phase of drying in a freeze dryer.

When implementing the method according to this invention the dissolution, filtration or sterilization by filtration and selection carried out analogously to known ujaut appropriate prepared bottles, which the facility is re-heated to 30-S. With this temperature marks phase starts freezing, which the maximum speed is completed in the desired freezing point. Next, a conventional method is carried out phase of drying. Due to the re-heating solutions significantly increases the dilution factor saturation that occurs due to reduce the size of water clusters. Thus, the ratio increased dissolution improves the hydration process. At fast cooling, first, water molecules do not have time to form a relatively large clusters, and, secondly, the molecules of the active component does not have sufficient time to be formed in the centers of crystallization. Thus, the resulting product is amorphous and can be restored without the formation of particles.

The solutions are heated to temperatures from 30 to S, in the preferred embodiment, the temperature is chosen in the range from 30 to 70 C.

Thus, the method according to the present invention allows to enter in the available volume is much higher concentrations. This reduces drying time and increase the efficiency of the method.

Obtained that is up to such saturation, can recover without the formation of particles.

This invention also relates to the production of liofilizatow substance, which is methanesulfonate 2-methyl-5-methylsulphonyl-4-(1-pyrrolyl)benzoylpyridine, through the implementation of the method described here (see example 1). This substance (EMD 96785), known, for example, from the application DE 4430861, an inhibitor IEE (sodium-hydrogen exchange), blocking ion pump Na+/H+in myocardial cells. This prevents pereokislenie cells during a heart attack, which causes death of tissue of the myocardium.

This invention also relates to the production of liofilizatow substance, which is the hydrochloride of N-[2-methyl-4,5-bis(methylsulphonyl)] benzoylpyridine described herein (see Example 2).

This substance (EMD 87580), known, for example, from application EP 0758 644 Al, is also an inhibitor of HBO, blocking ion pump Na+/H+in myocardial cells. This prevents pereokislenie cells during a heart attack, which causes death of tissue of the myocardium.

This invention also relates to the production of liofilizatow substance, which is methanesulfonate of 4-isopropyl-3-methylsulfonylbenzoyl description the om HBO.

This invention also relates to pharmaceutical preparations that contain at least one lyophilisate according to the invention. The pharmaceutical preparations may be used as medicaments in human and veterinary medicine. Suitable excipients are organic or inorganic substances that are acceptable for enteral (for example oral), parenteral or topical application and which do not react with lyophilisate, for example water, vegetable oils, benzyl alcohols, alkalophile, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or vaseline. Acceptable for oral administration forms are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, acceptable for rectal use are solutions, preferably oil-based or aqueous solutions, and also suspensions, emulsions or implants (capillary tube), and acceptable for topical application are ointments, creams or powders. These preparations can be sterilized and/or contain additives such as lubricants, preservatives, stabilizer shall itali, fragrances and/or most of the other active ingredients, for example one or more vitamins.

These preparations preferably contain lyophilizate, for example, for the manufacture of drugs for injection.

Even without further detail, it is understood that the person skilled in the art can use the above description in its broadest sense. Thus, the preferred embodiments of the present invention are provided solely to illustrate the past and in no way limit it.

All applications and publications referred to in this application previously and below, is included in this application as references.

Example 1

(a) 100 mg methanesulfonate 2-methyl-5-methylsulphonyl-4-(1-pyrrolyl)benzoylpyridine (inhibitor NVO) was dissolved in 20 ml of water by heating to accelerate the dissolution. Then the solution is sterilized by filtration and Packed into vials suitable for freeze-drying. During this process the solution is cooled to room temperature. In the freeze-dryer at room temperature load vials, after which it is again heated to 50C. Then spend freezing from 50 up to-50C in teenanal form then you can restore without the formation of particles.

b) Comparative example

100 mg methanesulfonate 2-methyl-5-methylsulphonyl-4-(1-pyrrolyl)benzoylpyridine again dissolved in 20 ml of water when heated to 40C. The solution is sterilized by filtration and filled during this process, the solution is cooled to room temperature.

The bottles are then cooled from room temperature up to-50C for one hour in the freeze dryer and freeze.

During this traditional process, the particles are formed even during lyophilization, which leads to the fact that lyophilizate when the recovery does not fully dissolve. To get the lyophilisate, comparable to a), it is necessary to reduce the concentration of 50 mg per 20 ml

Thus, this means that when implementing the method according to this invention it is possible to use a higher concentration of active ingredient, while receiving lyophilizate with a higher dissolution rate.

Example 2

100 mg of the hydrochloride of N-[2-methyl-4,5-bis(methylsulphonyl)]benzoylpyridine dissolved in 10 ml of water when heated to 40C. The solution is then filtered under sterile conditions and filled into FLAC the temperature.

The freeze dryer is cooled to-59S. Vials with solution heated to 40 C in an oven, then placed in a freeze-dryer, which is cooled to-50C. The solution is frozen as quickly as possible. Then the traditional way of conducting phase drying.

You can also heat the bottles in the freeze-dryer, followed by cooling (as described in example 1).

1. The method of obtaining freeze-dried with a high dissolution rate, wherein the pre-packaged for lyophilization solution, which, if necessary, pre-heated to accelerate the dissolution of the substance and filtered, if necessary, sterilized by filtration and then packaged in bottles, is subjected to repeated heating to a temperature of 30-S directly in vials placed in the freeze dryer, followed by a phase of freezing to the desired temperature freeze-drying over a period of time from 10 min to 4 h

2. The method according to p. 1, characterized in that the bottles containing the solutions are heated to a temperature of from 30 to 60C in the freeze dryer.

3. The method according to p. 1 or 2, characterized in that lyophilizate that moutoussis fact, what do you get lyophilized compounds selected from the group consisting of methanesulfonate 2-methyl-5-methylsulphonyl-4-(1-pyrrolyl)benzoylpyridine, hydrochloride N-[2-methyl-4,5-bis(methylsulphonyl)benzoyl]guanidine or the methanesulfonate of 4-isopropyl-3-methylsulfonylbenzoyl.

5. The lyophilisate with increased dissolution rate, wherein when receiving pre-packaged for lyophilization solution, which, if necessary, pre-heated to accelerate the dissolution of the substance, filtered or sterilized by filtration and then packaged in bottles, is subjected to repeated heating to a temperature of 30-S directly in vials of freeze-drying, followed by a phase of freezing to the desired temperature freeze-drying over a period of time from 10 min to 4 h

6. The lyophilisate of methanesulfonate 2-methyl-5-methylsulphonyl-4-(1-pyrrolyl)benzoylpyridine with improved restoration to its original state, wherein when receiving pre-packaged for lyophilization solution methanesulfonate 2-methyl-5-methylsulphonyl-4-(1-pyrrolyl)benzylguanine, which, if necessary, pre-heated to accelerate the dissolving is evania to a temperature of 30-S directly in vials of the freeze-dryer, followed by a phase of freezing to the desired temperature freeze-drying over a period of time from 10 min to 4 h

7. The lyophilisate of the hydrochloride of N-[2-methyl-4,5-bis(methylsulphonyl) benzoyl]guanidine with improved restoration to its original state, wherein when receiving pre-packaged for lyophilization solution of the hydrochloride of N-[2-methyl-4,5-bis(methylsulphonyl) benzoyl]guanidine, which, if necessary, pre-heated to accelerate the dissolution of the substance, filtered or sterilized by filtration and then packaged in bottles, is subjected to repeated heating to a temperature of 30-S directly in vials of the freeze-dryer, followed by a phase of freezing to the desired temperature freeze-drying over a period of time from 10 min to 4 h

8. The lyophilisate of methansulfonate 4-isopropyl-3-methylsulfonylbenzoyl with improved restoration to its original state, wherein when receiving pre-packaged for lyophilization solution methansulfonate 4-isopropyl-3-methylsulfonylbenzoyl, which, if necessary, pre-heated to accelerate the dissolution of the substance has shown that the bottles in the freeze-dryer, followed by a phase of freezing to the desired temperature freeze-drying over a period of time from 10 min to 4 h

9. Pharmaceutical preparation containing at least one lyophilisate obtained by the method according to PP.1-4 or described in paras.5-8.

 

Same patents:

The invention relates to the field of pharmaceutical industry and relates to lyophilized peptide/lipid product
The invention relates to medicine, namely to a restorative or cosmetic surgery and aesthetic dermatology

The invention relates to medicine and relates to pharmaceutical compositions containing a nucleotide analog, mannitol and modifying additive, which is sodium chloride or a polyol suitable for freeze-drying

The invention relates to medicine and sustainable, not containing albumin preparation of recombinant Factor VIII (rFVIII) in dried form, which has both crystalline and amorphous components, which after dilution water contains from about 65 to 400 mm glycine, 50 mm histidine, from 15 to 60 mm sucrose, 1 to 50 mm sodium chloride, 5 mm calcium chloride and from 50 to 1500 IU/ml rFVIII

The invention relates to compositions in the form of microcapsules or implants
The invention relates to the production of antibiotics, namely the technology of water-soluble salts of erythromycin, erythromycin phosphate

The invention relates to a method of stabilization and regulation changes in the peptide includes the sequence-Asp-Gly - or-Asn-Gly in the amino acid sequence in which the sequence-Asp-Gly - or-Asn-Gly - change operations on the fragment using a dehydration reaction or reactions desametasone and subsequent changes in-rearranged fragment using isomerization reactions, in particular, by way of regulation of such changes in the peptide, such as desulfuromonas hirudin or genuinely option

The invention relates to medicine

The invention relates to pharmaceutical industry and relates to a lyophilized pharmaceutical composition

The invention relates to new indole derivative of the formula I

where two of R1a, Rlb, Rlc, Rldindependently from each other denote H, F, I, Cl, Br, (C1-C4)alkyl, phenyl, phenyl-(C1-WITH4)alkyl, (C1-C4)alkoxy, phenyl-(C1-C4)alkoxy, phenyloxy, HE, -NR5aR5b, -SOn-R6c, n is 1-2, and are the same or different, and two other mean N; where all residues R5a, R5b, R6cif present in the molecule more than once, are independent from each other and may be each the same or different; one of R2and R3means -(CH2)p-CO-R8and the other denotes H, F, Cl, Br, or -(CH2)p-CO-R8; p is 0, 1 or 2; R8means-NR9R10, -OR10; A represents the bivalent residue of(C1-C4)alkyl, which is saturated or which contains a triple bond, or -(C1-C4)alkyl-CO-NH-, where the nitrogen is associated with R4; R4means phenyl, which is substituted by one residue R15bor pyridyl, which is unsubstituted or substituted14on the nitrogen atom; all their stereozoom

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds
The invention relates to medicine and AIDS, based on piracetam, affect the Central nervous system

The invention relates to the chemistry of biologically active compounds, and specifically to an improved process for the preparation of a derivative of hematoporphyrin, which is used as a photosensitizer for photodynamic therapy (PDT) of malignant tumors
The invention relates to the field of medicine and relates to a pharmaceutical composition having anti-depressive effect, and how you can get

The invention relates to a hydrazides in a series of bacteriochlorophyll and General formula I, where R1=COCH3CH(OH)CH3CH=CH2; R2=H,CH3C2H5; R3and R4=H, CH3, Tos, and the method of obtaining hydrazides I by reacting derivatives of bacteriochlorophyll and with additional anhydrous cycle with hydrazinehydrate and subsequent cyclization of the resulting intermediate hydrazide by adding to the reaction mass of hydrochloric acid; the proposed hydrazides have high photoinduced activity; in the absence of light irradiation hydrazides I at concentrations 6-15 times phototoxic not affect the growth of the cell culture

The invention relates to pharmaceutical industry and relates to a method of receiving anticonvulsant drug, which is a 3-benzylpyrrolidine-2,4-dione (1), namely, that the aminouksusnoy acid esters acelerou anhydrides of monoamino malonic acid in the presence of the solvent chloroform, the resulting product is converted into 3-alkoxycarbonylmethyl-2,4 in an alcohol solvent in the presence of ciclismo agent sodium alcoholate, the resulting product carbalkoxy by three times with boiling acetonitrile, at a concentration of product (V) 20-30 g/l in the reaction mixture, followed by cooling, filtration, distillation of acetonitrile, the resulting pyrrolidin-2,4-dione is administered in the reaction with the corresponding dialkylated of dimethylformamide or triakontameron, the resulting product is treated with benzylamine at 0-5oWith subsequent isolation of the target product

The invention relates to medicine, namely to drugs that improve blood circulation in the brain

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to the creation of a group of drugs vitamin b and lidocaine combined drug, analgesic, improves blood circulation, stimulates the regeneration of nerve tissue and antiallergic
Up!