Valganciclovir powder

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared invention refers to chemical-pharmaceutical industry, and concerns new solid pharmaceutical dosage forms of valganciclovir hydrochloride for oral administration after reduced in water. These new pharmaceutical dosage forms are applicable for treating or controlling viruses, such as herpes virus or cytomegalovirus.

EFFECT: new solid pharmaceutical dosage form shows high stability.

8 cl, 4 ex, 4 tbl

 

The present invention relates to novel solid pharmaceutical dosage forms of valganciclovir intended for oral administration after recovery in the water.

Valganciclovir is the active antiviral agent that is approved for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS), and for the prevention of CMV disease in kidney, heart and kidney transplantation and pancreas. Valganciclovir is L-monovasilis ester of ganciclovir and stable prodrug of ganciclovir, which is characterized by improved absorption. Such characteristics are especially valuable for suppression of herpes infection in patients with weakened immune systems, for which treatment is preferred oral administration. Valganciclovir described in detail in U.S. patent No. 6083953.

In the solid state when stored in ambient conditions valganciclovir has acceptable physical and chemical stability and light fastness. For storage no special requirements, except that you should avoid excessive humidity. Initial attempts to develop pediatric drug and drugs to patients, to the which it is necessary to change the dosage, were aimed at the preparation of liquid product intended for oral administration. However, data on short-term stability showed that the liquid dosage form is stable enough to provide the required shelf life when stored.

Initial attempts to develop dosage forms of valganciclovir, suitable for children and patients who need to change the doses were aimed at liquid preparation intended for oral administration. Data on short-term stability showed that the liquid dosage forms stable enough to provide the required shelf life during storage. Therefore, efforts have focused on developing powder dosage forms intended for restoration and water provide an acceptable shelf life when stored for valganciclovir and obtained (recovered) liquid dosage forms. To improve the characteristics of stability and processability powdered dosage forms and characteristics of the stability of the recovered liquid dosage form, the method of dry granulation mixture was replaced by a method of wet granulation mixture.

Because valganciclovir it is soluble in what Isla environment, solid pharmaceutical dosage form must include an organic acid in a quantity sufficient to solubilize and stabilize valganciclovir in a predetermined amount of water for the intended shelf life during storage for the retrieved (restored) liquid dosage forms. Found that hygroscopic organic acid decompose the solid pharmaceutical dosage forms of valganciclovir.

The present invention was based on the task of getting the drug valganciclovir intended for use in pediatric patients and patients who need to change the dosage.

This task can be solved by using solid pharmaceutical dosage forms of valganciclovir intended for oral administration after recovery in the water.

The present invention relates to a solid pharmaceutical dosage form intended for oral administration after recovery in water, comprising (a) a therapeutically effective amount of valganciclovir; and (b) nephroscopes organic acid in a quantity sufficient to stabilize valganciclovir in a pre-determined amount of water.

The present and the finding also relates to a liquid pharmaceutical dosage form, intended for oral administration, comprising (a) a therapeutically effective amount of valganciclovir; (b) a predetermined amount of water; and (C) nephroscopes organic acid in a quantity sufficient to stabilize valganciclovir in a pre-determined amount of water.

The present invention also relates to solid or liquid dosage form, intended for use for the treatment of herpes simplex or diseases mediated by cytomegalovirus.

The present invention also relates to a method for preparing solid pharmaceutical dosage forms intended for oral administration after recovery in water, comprising mixing (a) a therapeutically effective amount of valganciclovir; and (b) nephroscopes organic acid contained in a quantity sufficient to stabilize valganciclovir in a pre-determined amount of water.

Solid pharmaceutical dosage forms intended for oral administration after recovery in the water, have the advantage that they allow you to provide patients with the necessary dose. For example, while valganciclovir comes in the form of tablets by weight of 450 mg, for peror the form of further introduction, liquid dosage forms can be prepared in a wide range of concentrations. Preferred liquid dosage form can be prepared at a concentration of 50 mg/ml and using it to provide a wide range of doses for children and patients who need to change the dosage. Container for liquid dosage forms can be provided to a calibrated metering device for issuing a corresponding number of fluid containing the required dose.

When used in the present invention the following terms have the specified values.

The expression "effective amount nephroscopes adds volume agent" means the number nephroscopes lash thickening agent, sufficient to facilitate the preparation of solid pharmaceutical dosage forms proposed in the present invention. The presence nephroscopes lash thickening agent is optional, but the inclusion of nephroscopes lash thickening agent makes the method of preparation of solid pharmaceutical dosage forms easier and can provide the necessary volume and the sweet taste of the finished product.

The term "disease", in particular, includes any pathological condition of the subject, defined in the present invention. Thus, in the present invention C is bolovanje" includes any virus or related disease, which is treatable by valganciclovir or its pharmaceutically acceptable salts.

The expression "nephroscopes organic acid in a quantity sufficient to stabilize valganciclovir in water"refers to the number nephroscopes organic acid required to reduce the pH of the liquid pharmaceutical dosage forms of valganciclovir thereby stabilizing valganciclovir in a pre-determined amount of water.

The expression "pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient and the like, means pharmacologically acceptable and generally non-toxic to the subject when using the number in which you enter a particular connection.

The expression "a predetermined amount of water" means any amount of water needed to restore the solid pharmaceutical dosage forms proposed in the present invention, in a liquid pharmaceutical dosage form intended for oral administration. The amount of water may vary depending on the required concentration of valganciclovir in aqueous solution. The necessary concentration of valganciclovir in aqueous solution may depend on factors such as Conques is to maintain the subject, treated treated disease, duration of treatment, etc.

The term "subject" includes humans, mammals, non-human (such as dogs, cats, rabbits, cattle, horses, sheep, goats, pigs and deer), and animals that are not mammals, such as birds, fish, etc. Preferably, if the entity represents a person or a mammal, not a person, and more preferably, if the subject is a human.

The term "therapeutically effective amount" as applied to valganciclovir means the amount of compound or its pharmaceutically acceptable salt that, when introduced to the needy at the subject effective to treat, prevent, facilitate the flow or mitigate symptoms of the disease.

The term "treatment" means any treatment of a disease in a subject and includes: (1) prevent the occurrence of disease in a subject which may be predisposed to the disease but has not yet observed or not symptoms of disease, such as preventing the appearance of clinical symptoms; (2) suppression of the disease, such as a stop of its development; or (3) relieving the disease course, such as regression of symptoms.

Valganciclovir the hydrochloride (valganciclovir. HCl, Valcyte®) is a hydrochloride of L-valovogo ester (prodrug) of ganciclovir that exists as a mixture of two diastereoisomers. After oral administration, both diastereoisomer quickly turned to ganciclovir by intestinal esterases and liver. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits the replication of human cytomegalovirus in vitro and in vivo. Ganciclovir is approved for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) and for the prevention of CMV disease in kidney, heart and kidney transplantation and pancreas. Valganciclovir is available in tablets of 450 mg, intended for oral administration. Each tablet contains 496,3 mg valganciclovir (equivalent to 450 mg of valganciclovir), and the inactive ingredients microcrystalline cellulose, povidone K-30, crosspovidone and stearic acid. Film coating on a pill that contains dye Opadry® Pink.

Valganciclovir is a white or almost white crystalline powder and has a molecular formula C14H22N605·HCl and a molecular weight equal to 390,83. The chemical name of valganciclovir - monohydrochloride 2-[(2-am is but-1,6-dihydro-6-oxo-N-purine-9-yl)methoxy]-3-hydroxypropionic ester L-valine. The chemical structure of valganciclovir below.

The solubility of valganciclovir (active pharmaceutical ingredient, API) in aqueous solution depends on the pH. Valganciclovir is a polar hydrophilic compound with equal 70 mg/ml solubility in water at 25°C and at pH=7.0 and coefficient distribution in the system n-octanol/water equal 0,0095 at pH=7.0. The value of pKa of valganciclovir equal to 7.6. Valganciclovir it is soluble in acidic media and the maximum solubility of greater than 200 mg/ml, is observed in the pH range 4-6. The stability of valganciclovir is greatest at pH<3,8.

Valganciclovir can exist in one of two crystalline forms (called X and Y) and in amorphous form. Industrial technology for valganciclovir gives only the form y Form Y stable in various pharmaceutical processes used to prepare the powder for oral solution. All games valganciclovir used in the manufacturing to develop, conduct clinical trials, studying the stability and the Desk, was a form of Y. For the objectives of the present invention can use any polymorphic or amorphous form of valganciclovir is hydrochloride, because the final product is liquid. You can also use any diastereoisomer and the mixture diastereoisomers.

Valganciclovir is moderately hygroscopic and low relative humidity humidity valganciclovir changes slightly. During curing in an environment with relative humidity, which constitutes 80%of the mass of valganciclovir the increase in weight amounts to about 3% (full water content reaches about 8%). It is reversible hygroscopic and environmental conditions depending on the water content in valganciclovir and relative humidity, it absorbs or emits water.

Therapeutically effective amount or dose of valganciclovir in the context of the present invention may vary within wide limits. While valganciclovir comes in the form of tablets weighing 450 mg, intended for oral administration, solid pharmaceutical dosage forms can be restored to a liquid pharmaceutical dosage forms, which can be prepared in a wide range of concentrations for the treatment of children and patients who need to change the dosage. A container for solid/liquid dosage forms can be provided to a calibrated dosing device for issuing sootvetstvuyuschego quantities of liquid, containing the required dose. These doses are in each case can be chosen according to individual requirements depending on the patient and pathological conditions treated.

Usually the number of valganciclovir contained in the solid pharmaceutical dosage form may be in the range of from about 10 to about 90%, preferably from about 25 to about 75%, more preferably from about 35 to about 60% and most preferably about 46 wt.% in terms of total weight of the composition.

Usually liquid pharmaceutical dosage forms, which can be recovered from the solid pharmaceutical dosage forms using a predetermined amount of water can be prepared at concentrations of valganciclovir (as free base)comprising from about 10 to about 90 mg/ml, preferably from about 25 to about 75 mg/ml, more preferably from about 35 to about 65 mg/ml, and most preferably about 50 mg/ml

Nephroscopes organic acids in the context of the present invention it is possible to choose from among a variety of nephroscopes organic acids. As stated above, hygroscopic organic acid decompose the solid pharmaceutical dosage forms in which chanceconstrained. At ambient temperature and a relative humidity of approximately 60-75%proof, non-hygroscopic organic acid absorbs less than 1 wt.% water.

In one embodiment, nephroscopes organic acid is an amino acid, preferably an amino acid containing an additional carboxypropyl, such as glutamic acid or adipic acid.

In another embodiment, nephroscopes organic acid selected from the group comprising fumaric acid, succinic acid, adipic acid. Preferably, if nephroscopes organic acid is a fumaric acid or succinic acid. More preferably, if nephroscopes organic acid is a fumaric acid.

Nephroscopes organic acid is contained in a quantity sufficient to stabilize valganciclovir in solid pharmaceutical dosage form. Valganciclovir has equal to 70 mg/ml solubility in water at 25°C and at pH=7.0 and it is soluble in acidic media and the maximum solubility of greater than 200 mg/ml, is observed in the pH range 4-6. Usually the number nephroscopes organic acids reduces the pH of the recovered solution valganciclovir the reed to pH< of 3.8 and most preferably to pH=3,0.

Solid pharmaceutical dosage form optionally may contain an effective amount nephroscopes lash thickening agent. As stated above, hygroscopic lash thickening agents decompose valganciclovir in solid pharmaceutical dosage forms. The presence nephroscopes lash thickening agent makes the method of preparation of solid pharmaceutical dosage forms easier and can provide the necessary volume and the sweet taste of the finished product. Nephroscopes lash thickening agent in the context of the present invention it is possible to choose from among a variety of nephroscopes lash thickening agents. At ambient temperature and a relative humidity of approximately 60-75%proof, non-hygroscopic lash thickening agent absorbs less than 1 wt.% water. Usually nephroscopes lash thickening agent selected from the group comprising mannitol and lactose. Preferably nephroscopes lash thickening agent is a mannitol.

Nephroscopes lash thickening agent may be contained in the solid pharmaceutical dosage form in an amount constituting from about 10 to about 90%, preferably from about 30 to about 70%, and more preferably from about 40 to when is Erno 60 wt.% in terms of total weight of the composition.

The preferred implementation of the present invention are presented in table 1. Solid pharmaceutical dosage form intended for oral administration, is a powder that restores the predetermined amount of purified water and obtain a liquid pharmaceutical dosage form. The vial contains approximately 5,515 g valganciclovir in 12 g of powder for a recovery solution that is designed for oral administration. After recovery solution volume of 100 ml In 1 ml of the recovered solution containing 55,15 mg valganciclovir, which corresponds to 50 mg of the free base of valganciclovir. The concentration of valganciclovir in the form of free base in the recovered solution is 5.0%. Valganciclovir and inert fillers soluble in aqueous solvent. Powdery mixture can be prepared by conventional pharmaceutical techniques, including wet granulation. The drug is preferably sold in the bottle of brown glass with screw caps, available for child-resistant.

Table 1
The pharmaceutical composition of valganciclovir as OSCE and the recovered solution
ComponentsThe contents of a single dose mg/120 mgThe mixture is placed into the vial, g/vialThe recovered solution, mg/ml
Valganciclovir·HCl55,1515,515155,151
Povidone K2,000,2002,00
Fumaric acid2,000,2002,00
Sodium benzoate1,000,1001,00
Sodium salt of saccharin0,250,0250,25
Mannitol57,805,78057,80
Supplement with a taste of fruit1,800,1801,80
Purified water22 of 0.91 ml
Only120 mg12,000 g1,000 ml
1Equivalent to 50 mg of valganciclovir (as free base), calculated on the dry matter
(salt with HCl=MM (molecular weight) 390,83; base = MM 354,36)
2Removed during processing

Pharmaceutical dosage forms proposed in the present invention, can be prepared in accordance with the following examples. The examples are presented only to illustrate and not to limit the methods of preparation of compounds and compositions proposed in the present invention.

Examples

In the context of the present invention the following examples are presented for illustrative descriptions of solid and liquid pharmaceutical dosage forms.

Example 1

Comparison of drugs valganciclovir type I and type II carried out below in table 2.

Table 2
Powder for oral solution - comparison drugs
Type IType II
mg/250 mg (restored = 1 ml)mg/120 mg (restored = 1 ml)
The number of medicationJ05F01-03F01-02
Valganciclovir55,15155,15155,151
Anhydrous citric acid9,50--
Sodium citrate0,40--
Sodium benzoate1,001,001,00
Fumaric acid-2,002,00
Povidone K-2,002,00
Sodium salt of saccharin0,250,250,5
Supplement with strawberry #E5,00--
Supplement with a taste of fruit #11900-31-1,801,80
The crystalline maltose178,70--
Mannitol-57,8057,80
Purified water-22
Full weight in 1 ml250,00 mg120,00 mg120,00 mg
The total weight of the vial15,00 g14,40 g12.00 g
The amount of added water51 ml109 ml91 ml
The full amount of the recovered substance60 ml120 ml100 ml
Vial: Type I brown glass120 ml120 ml120 ml
1Equivalent to 50 mg of valganciclovir (as free base), calculated on the dry matter
2Removed during processing

Preparations of type I

For the preparation of type I used the following inert fillers. Anhydrous citric acid combined with sodium citrate and received a buffer system that supports an acidic environment. Acidic environment contributes to the stabilization of valganciclovir because valganciclovir has the greatest stability in aqueous solution at pH of about 3.8 or below. Sodium benzoate used as preservatives and sodium salt of saccharin used as an artificial sweetener. Maltose, crystalline disaccharide, was used as a lash thickening agent (diluent) and to provide grinding and sweet taste. Supplement with strawberry used as flavor additives for oral solution.

For preparation of the drug of type I, drug J05, used the following method. In stage 1 sodium citrate and sodium salt of saccharin about aivali separately and mixed in the mixer with a part of the crystalline maltose. In stage 2 the mixture obtained in stage 1, was mixed with milled anhydrous citric acid and another portion of the crystalline maltose and Supplement with strawberry taste. At stage 3 the mixed material was sieved and mixed with sifted sodium benzoate and a portion of the crystalline maltose. In stage 4 the remainder of crystalline maltose and valganciclovir was mixed with a mixed material obtained in stage 2 and then this mixed material was screened. The mixed material obtained in stage 3, was placed between two layers of a mixed material obtained in stage 4, and mixed with the resulting mixture. 15 g of the final mixture was placed in a bottle and shut the specified cover.

Example 2

Drugs type II

From the drug of type I to the drug of type II passed and the drug of type II were changes to improve the performance stability of solid pharmaceutical dosage forms and the recovered liquid pharmaceutical dosage forms intended for oral administration. Differences between preparations of type I and type II are described below.

The observed decomposition of the drug of type I has been attributed to the interaction of valganciclovir/citric acid in the solid pharmaceutical dosage form. Citric acid is hygroscopic body of the standard acid and apparently, decompose valganciclovir in solid dosage form. Fumaric acid is less hygroscopic organic acid and therefore it was chosen to replace the system citric acid/sodium citrate drug of type II.

The observed decomposition of the drug of type I has also been attributed to the interaction valganciclovir/maltose in the recovered liquid pharmaceutical dosage form intended for oral administration. Maltose, apparently, decompose valganciclovir in liquid dosage form. Maltose was replaced with mannitol, polyhydric alcohol, which does not cause decomposition of valganciclovir. Povidone K (polyvinylpyrrolidone) was added as a binder, and water as the granulating fluid to transition from dry mixing technology by wet granulation. The use of technology wet granulation improves the flowability of the dosed mixture of the drug of type II. In the offer for sale the drug instead of the additive with strawberry used additive with the flavor of the fruit. The total weight of the powder, put it in a bottle, changed from 15,00 g, drug J05 (type I), 14,40 to g, the drug F01-03 (type II). Then the mass is offered for sale drug drug F01-02 (type II)was reduced to 12.00 g to increase with the rim space above the drug to improve recovery when shaken.

Example 3

The method of preparation of type II

The party prepared clinical drug of type I at first was based on the dry powder mixture. After changes in the composition through the introduction of other inert fillers, it was found that the flowability of the final powder mixture is not suitable for acceptable processing characteristics. When using wet granulation flowability of the final powder mixture is significantly improved. As for the preparation of commercially available tablets valganciclovir 450 mg used water wet granulation using povidone K as a binder, this technology was used as the basis for the preparation of solid pharmaceutical dosage forms for recovery using a predetermined amount of water.

In the method proposed in the present invention, the active substance is first mixed with povidone K, fumaric acid and mannitol. Sodium benzoate and sodium salt of saccharin were dissolved in purified water, which was used as the granulating solution. The granulate was prepared in the mixer with a large shear force. Flavoring was added to the dried and crushed to granules during the last mixing and received the mixture to put in the bottles. When the bit is the development of technologies used in different conditions: applied and not applied binder, changed the order of his addition and the order of addition of sodium benzoate and sodium salt of saccharin.

In the absence of a binder granulate was very fragile and when the grinding has formed an excessive amount of fine particles. The addition of a binder (povidone K) as granulating solution and added in dry form led to the same results. To facilitate processing povidone K was added in dry form.

Sodium benzoate and sodium salt of saccharin was added to the ultimate ground of the granulate in the form of dry powders and dissolved in purified water to the stage of granulation. Determination of sodium benzoate and uniformity enable showed that the addition of a preservative in the solution and granulation of powders in the mixer with a large shear force leads to the value of %TOC (relative standard deviation) for preservative component <2%. The addition of dry sodium benzoate in the final powder mixture leads to unacceptable fluctuations in the values. To ensure quantitative transfer of all sodium benzoate critical rinse the container for granulating solution portion of purified water.

Example 4

Party for stability studies

The stability data for typical batches of medicines of type I and type following table 3 (for powder recovery) and table 4 (for the recovered solution). Powder type II and rebuilt the solution of type II have better stability characteristics in terms of release of valganciclovir and full amounts of impurities.

Table 3
Powder for oral solution - comparison between stability
MedicationPowder type IPowder type II
Storage conditionsThe percentage indicated on the label) of valganciclovirThe full content of impuritiesThe percentage indicated on the label) of valganciclovirThe full content of impurities
Before storage100,4%1,4%102.1%1,1%
12 months at 25°C/60% RH*99,4%2,0%100,0%1,2%
18 months at 25°C/60% RHthe 98.9%2,9% 100,0%1,3%
24 months at 25°C/60% RHto 96.9%4,3%101,9%1,4%
* Relative humidity

Table 4
The recovered solution - comparison between stability
MedicationThe recovered solution of type IThe recovered solution of type II
Storage conditionsThe percentage indicated on the label) of valganciclovirThe full content of impuritiesThe percentage indicated on the label) of valganciclovirThe full content of impurities
Before storage100,0%1,42%102,1%1,1%
1 month at 5°C99,9%1,69% 97,0%1,1%
2 months at 5°C99,9%2.20%98,1%1,2%
3 months at 5°CNo dataNo data99,2%1,3%

Optimization of the method

Prepared two demo party powder of valganciclovir for recovery. The first demo party (party 1) was prepared to assess the cooking method receive 5 kg of This party were placed in vials manually. During the preparation of the party there were no significant difficulties. The second demonstration batch (batch 2) was prepared to evaluate ways of cooking with getting to 17.25 kg For the second party's task was to assess the stage of mechanical packaging vials. For this demo party successfully held under granulation, drying and mixing. Packaging powder using auger filling device was successful. Throughout the study without any difficulty, the mass of powder, placed into vials remained constant.

Optimized method of preparation of powdered valganciclovir (batch weighing 30 kg) in local dry mixing, the addition of granulating solution, wet granulation, wet grinding, drying in the fluidized bed, dry grinding, mixing and filling bottles. To optimize the parameters of each stage of the preparation of powdered valganciclovir to restore prepared a total of 9 experimental batches on an industrial scale.

Method of cooking

Valganciclovir, mannitol (Parteck M200), povidone K and fumaric acid were placed in a mixer/granulator with a large shear force. After dry mixing in a granulator with a large shear force was added granulating solution. Granulating the solution contained sodium benzoate, sodium salt of saccharin and purified water and it was prepared prior to the stage of dry mixing. To transfer 100% of sodium benzoate in the final preparation is critical to move your entire granulating solution. After granulation to improve transportation flow of wet granular grinded in the mill Fitzmill and directed into the drying apparatus with fluidized bed. Comparing ground and unground wet granulate. Received from the drying apparatus of the dried granulate was grinded in the mill Fitzmill. Then the granulate was mixed with pre-mixed flavoring agent. Comparing the use of pre-paremesan the th flavoring and adding flavorings directly into the mixture. Then the powder mixture was placed in vials and Packed. Addition and transportation of the material during preparation was performed using a vacuum transportation system.

When the studies recorded and evaluated these parameters the following stages:

(a) granulating the dry mix (distribution of particle mixtures in size);

(b) wet granulating [volume of water in a granulating solution, the rate of addition of solution (182-558 g/min)] until the end of the granulation (time, HP, visually);

(C) drying in a fluidized bed [finish drying (PPP value - losses during drying);

(g) a dry grinding at a speed of 1000-4500 rpm;

(d) the final mix [the length of the final mixing (adding flavorings), 5-15 min, the homogeneity of single doses, the determination of the content of active pharmaceutical ingredient and preservative, sieve analysis, bulk density and density utracki];

(e) filling of the vial (the speed of the auger, 400-800 rpm);

(W) a study of flowability; the flowability of the powder was evaluated by caking by determining the bulk density. To assess the flowability of the samples dry milled mixture, finite mixture and of the drug, placed in vials, used index values Carr (IR) and was calculated by the following equation:

IR=(density utracki - bulk density×100)/density utracki

The values of IR subjected to dry grinding of the samples was in the range of from 12.66 to 39,19.

After dry grinding all parties observed a different distribution of particle sizes. These results were attributed to the fact that each party had different conditions granulation (i.e. the volume of granulating solution, the duration of the addition, the feed speed, download speed, upload speed and so on).

Data

The distribution of particle sizes for finite mixture parties #303 #493 corresponded well with the data of the sieve analysis for the second demo party. Batch #303 and #493 was a bit more of fine particles (<75 μm)than in the second demo party. For the preparation of granulating solution for both parties used the amount of water in the range from 2.7 to 3,45 kg Duration of the addition of granulating solution was in the range of 4-5,5 minutes processing time wet weight ranged from 1.5 to 2 minutes Final humidity (PPP) samples taken from the hole of the sample, ranged from 1.8 to 2.13%.

The values of IR for samples of finite mixture was in the range of from 17,44 to 33,80, showing that the flowability was fair to very poor. Party #283, #293 and #473, which contained a large number of particles with a size of 250 μm, had the best sauces is d, than the party, containing a large number of small particles.

Not found significant differences flowability of material samples taken at the beginning, in the middle and at the end of the filling of vials for each lot #283 and #293. The flowability of the materials of these parties was a little different. The values of IR ranged from 19,10 to 24,18, indicating a satisfactory flowability.

Data analysis

All parties had an acceptable homogeneity of values %CCA (relative standard deviation), less eligibility criteria, is 5.0%.

The average content of sodium benzoate in lot #293 amounted to 85.5%, which met the eligibility criteria. The party did not conduct the flushing water container for sodium benzoate, which could lead to the loss of sodium benzoate. So for a full migration sodium benzoate should include the stage of washing.

For the preparation of granulating solution for parties #303 and #323 used to 1.7 kg of water. Both parties received the content of sodium benzoate was low. This could be attributed to the amount of water insufficient to dissolve sodium benzoate. Therefore, for the complete dissolution of sodium benzoate need more water.

Study duration stirring for party #333 showed that benzoe the sodium and valganciclovir are characterized by good uniformity of content in the investigated time points (5, 7.5 and 10 min). However, data on the duration of mixing for party #493 show that valganciclovir has better uniformity of content at time 5 and 10 min, and sodium benzoate has the best uniformity of content at time of 7.5 and 10 minutes So I chose the duration of mixing is equal to 10 min, to ensure a good uniformity of content and for valganciclovir, and sodium benzoate. The use of pre-mixed flavours for party #283 has not led to a significant improvement in the uniformity of the content of flavour in the product. So in the end the way did not include preliminary mixing flavorings. The vials were filled with machines to fill All Fill Servometer.

In General, physical and analytical data were acceptable to all parties. More significant fluctuations in weight of the final powder mixture was observed for party #323 where to fill vials used auger speed of 600 rpm So for stage fill chose the speed of the screw equal to 450 rpm

Recommendations for the preparation technology, intended for registration of parties

In the method of dry mixing mannitol (Parteck M200), povidone K, powdered fumaric acid and valganciclovir for what was rurali in the granulator PMA 65 were subjected to dry mixing for 7 min at a rotation speed of the impeller, equal to 200±50 rpm, and the rotation speed of the chopper, 1000±50 Rev/min For the addition of a solution and wet granulation just wanted to 3.45 kg of water (granulating solution and rinsing). Granulating solution must be added in PMA 65 for 4±0.5 min at a speed of rotation of the impeller is equal to 200±50 rpm, and the rotation speed of the chopper, 1000±50 rpm Wet mass is stirred for a further 1±0.5 min with the same settings of the impeller and chopper. Wet grinding is not required.

After drying the granulate from PMA 65 directed into the fluidized bed dryer and dried until PPP, equal from 1.3 to 3.0%, when the control value is equal to 2.25%. The required temperature of the drug is 50°C (acceptable range is from 48 to 52°C). For grinding the dried granules were grinded in the mill Fitzmill at a speed equal to 2400±50 rpm, using plate #0 with forward blades. Mixing is not required pre-mixed flavoring. Milled granules should be mixed with the additive with the flavor of the fruit in the hopper mixer with a volume of 3 cubic feet for 10 minutes at a speed of 10 rpm For packaging of the drug vials used machine for powder filling All-Fill when the speed of the screw equal to 450 rpm and speed dosing at which trojstva, 100 Rev/min

To estimate the parameters set for each stage of the preparation of powdered valganciclovir for recovery in industrial scale (30 kg) were prepared only three registration batches (batch #024, #034 and #044). Bulk density and density utracki final mixes for parties #024, 034 and density of the final mixes for parties #024, 034 and 044 were similar. For all parties flowability of the final mixture was fair to poor (index values Carr equal from 21,79 to 31,46).

The results for valganciclovir and sodium benzoate for parties #024, #034 and #044 met the eligibility criteria. The homogeneity of the mixtures ranged from 96,4 up to 102.9% for valganciclovir and 96,4 to 100.0% for sodium benzoate. Values %CCA for valganciclovir and sodium benzoate were in the range from 0.3 to 1.2%. All the results indicated an acceptable homogeneity of values %TOC), less eligibility criteria, is 5.0%.

Using the parameters established for lots of research, successfully prepared three registration batches of powdered valganciclovir for recovery. All three parties met the eligibility criteria. Data collected during process operations, and the results showed that the method of cooking is all right is regulated and ensures the uniform quality of the drug in accordance with the requirements of GMP (established manufacturing practice).

The effectiveness of the preservative

The recovered solution contains sodium benzoate in a concentration of 0.1%. This solution in glass vials characterized satisfactory bactericidal and fungicidal efficacy of the preservative, which ensures that an acceptable germicidal efficiency will be maintained during the period of use of the drug.

Comparative bioavailability of clinical drug and commercially available drug

The main goal of this study was the determination of the biological equivalence of ganciclovir from intended for oral administration of a solution of valganciclovir with the addition of tasteful fruit (F01-02) and from Valcyte, commercially available tablets of 450 mg of the drug valganciclovir at the dose of 900 mg, administered not on an empty stomach. The second objective was the comparison of the systemic exposure of ganciclovir from intended for oral administration of a solution of valganciclovir with the additive with strawberry (J05) and intended for oral administration of a solution of valganciclovir with the addition of tasteful fruit (F01-02) at the dose of 900 mg

For both cases, CPD 0-24 (area under the curve over a period of time 0-24 h) and Cmax (maximum peak concentration), 90% confidence interval (CI) for the average relationship value is s for tablet designed for oral administration of the solution with the addition of tasteful fruits are in the range of acceptability, from 80 to 125% ([96, 104] and [89, 101] for CPD 0-24 and Cmax, respectively). Therefore, we can conclude that biological equivalence tablet designed for oral administration of the solution with the additive with the flavor of the fruit content of ganciclovir plasma. According to the average values of CPD for ganciclovir intended for oral administration solution with the addition of tasteful fruit provides similar effects for which it is known that they are safe and effective. The values of Cmax and CPD for ganciclovir in drugs with the addition of tasteful fruits and Supplement with strawberry taste very close to each other and lead to a 90% CI for average values of the components from 96 to 109% and from 94 to 101%, respectively.

Although presented a number of embodiments of the present invention, it is obvious that the main implementation options you can change and get more options for implementation, in which the present invention is used without deviating from the essence and scope. It is implied that all such modifications and changes are included in the scope of the present invention, which is defined by the attached claims rather than specific implementation options, which are given as examples.

1. Solid pharmaceutical dosage form intended for oral administration the donkey recovery in the water, including:
(a) a therapeutically effective amount of valganciclovir;
and
(b) fumaric acid is contained in a quantity sufficient to reduce the pH of the recovered solution valganciclovir to a pH of approximately 3.8 or below.

2. Solid dosage form according to claim 1, in which valganciclovir contained in an amount constituting from about 10 to about 90 wt.% in terms of total weight of the composition.

3. Solid dosage form according to claim 1, additionally comprising an effective amount nephroscopes lash thickening agent.

4. Solid dosage form according to claim 3, in which nephroscopes lash thickening agent selected from the group comprising mannitol and lactose.

5. Solid dosage form according to claim 3 or 4, in which nephroscopes lash thickening agent is a mannitol.

6. Solid dosage form according p-5, in which nephroscopes lash thickening agent is contained in an amount of up to about 90 wt.% in terms of total weight of the composition.

7. Solid dosage form according to claims 1-6, which has the following composition:

ComponentsThe contents of a single dose mg/120 mg
In valganciclovir. Cl 55,151
Pavido C2,00
Fumaric acid2,00
Sodium benzoate1,00
Sodium salt of saccharin0,25
Mannitol57,80
Supplement with a taste of fruit1,80
1Equivalent to 50 mg of valganciclovir (as free base), calculated on the dry substance.

8. The use of dosage forms according to any one of claims 1 to 7 for the preparation of medicines intended for the treatment of herpes simplex and diseases mediated by cytomegalovirus.



 

Same patents:

FIELD: medicine.

SUBSTANCE: strain "АС-21/07" of Aujeszky's disease virus was deposited in collection of VGNKI under registration number "АС-21/07"-DEP. Strain is obtained from original strain MK-25 by selection. In culture of cells PSGK-60 and PSGK-60S virus 19-20 passage is accumulated to 8.0-8.5 lg TCD50/cm3.

EFFECT: strain is attenuated for pigs, sheep, rabbits and possesses high biological, antigenic and immunogenic activity in native form and after inactivation.

2 dwg, 3 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: method is realised by treating a compound of formula

with boronic acid or ether thereof of formula

,

in which two OR15 groups together with the boron atom with which they are bonded form a pinacolato boronate ester group in the presence of a Pd catalyst. The invention relates to a method of producing a pharmaceutically acceptable salt of thieno[3,2-d]pyrimidine of formula

.

The invention also relates to a pharmaceutical composition, having phosphatidyl inositol-3-kinase inhibitor activity, containing thieno[3,2-d]pyrimidine of formula (I) as an active ingredient, a method of preparing said composition and use of thieno[3,2-d]pyrimidine of formula (I) or pharmaceutically acceptable salt thereof in producing a medicinal agent for inhibiting phosphatidyl inositol-3-kinase.

EFFECT: use of the derivative as a phosphatidyl inositol-3-kinase inhibitor.

11 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmacology, namely to medications based on peptides. Composition includes 0.01-0.03 mg per one therapeutic dose of endogen interferon inductor - dipeptide of glutamic acid, selected from group, which includes alpha-glutamyl triptophan, gamma-glutamyl triptophan and alpha-lysyl glutamine, Composition also contains co-inductor of endogen interferon - glycyrrhizic acid, taken in form of sodium or ammonium salt in quantity 50-500 mg per one dose.

EFFECT: invention insures formation of prolonged antiviral resistance, necessary for fast and effective elimination of virus-causative agent and elimination of disease symptoms.

3 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel cyclic peptide compound of pharmaceutically acceptable salt thereof, having activity against hepatitis C virus, based on inhibiting activity against replication of the hepatitis C virus RNA replicon, a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof, and use of the compounds or pharmaceutically acceptable salt thereof to prepare a medicinal agent with anti-HCV activity.

EFFECT: high efficiency of the compounds.

9 cl, 19 tbl, 259 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel antiviral active components - substituted indoles of general formula 1 and pharmaceutically acceptable salts thereof, which can be used to treat and/or prevent viral diseases caused by hepatitis C virus (HCV). In general formula , R1 denotes a hydrogen atom, optionally substituted C1-C4alkyl, C6cycloalkyl, phenyl, ethoxycarbonyl, nitro group; R2 denotes a hydrogen atom; R3 denotes N-mono- or N,N-disubstituted 1-methylene-piperidine-3-carboxamide of general formula 1a or N-mono- or N,N-disubstituted 1-methylene-piperdine-4-carboxamide of general formula 1b; R4 denotes a hydrogen atom, optionally substituted C2-C3alkyl, a -CH2-R12 group, where R12 denotes a hydrogen atom or phenyl which is optionally substituted with halogen or C1-C4alkyl; or R2, R3, and R4 together with atoms with which they are bonded form a substituted azaheterocycle of general formula 1.2; or R2 and R3 together with carbon atoms with which they are bonded form a substituted 2,3,4,9-tetrahydro-1H-carbazole of general formula 1.1, in which R1 denotes methyl, ethoxycarbonyl, nitro group; R4 denotes a hydrogen atom, methyl, C2-C3alkyl substituted with N-benzylamine; R7 and R8 denote hydrogen atoms or R7 and R8 together with a carbon atom with which they are bonded form a C=O group; R5 and R6, which are optionally identical, denote a hydrogen atom, optionally substituted C1-C3alkyl or C3-C6cycloalkyl; or R5 and R6 together with a nitrogen atom with which they are bonded form an optionally substituted 5- or 6-member azaheterocyclyl containing one or two nitrogen atoms, etc.

EFFECT: improved properties of compounds.

11 cl, 1 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to veterinary science, and concerns inactivated chimeric vaccines and related methods of application. Substance of the inventions involves an inactivated chimeric flavivirus containing a first flavivirus representing a yellow fever virus in which nucleotide sequences coding pre-membrane and membrane proteins are substituted by nucleotide sequences coding pre-membrane and membrane proteins a second flavivirus representing a West Nile fever virus. The inventions also involve an immunogenic composition and a vaccine for protection of animals from the flavivirus infections, involving the inactivated chimeric flavivirus.

EFFECT: development of the advanced immunogenic composition and the vaccine on the basis of the inactivated chimeric flavivirus.

14 cl, 3 ex, 5 tbl

Antiviral agent // 2436583

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to antiviral agents. What is offered is application as an antiviral agent for treating ARVI, including influenza, of soapy amphiphilic high-polymer RNA Saccharomyces cerevisiae recovered from dry baker's yeast with the use of alkali titred oleic acid, or with the use of sodium dodecyl sulphate by processing of the recovered RNA with oleic acid (the proposed market name of the agent is Vitalang-2). The antiviral properties of the agent have been tested at the time of influenza epidemic, and a positive result has been shown positive.

EFFECT: low-toxic properties of the agent and reduced time for treating the ARVI to 1 day are shown.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns an immunomodulatory drug preparation showing antiviral properties. Substance of the invention consists in the fact that the offered drug preparation contains sodium nucleinate 2 to 50 mg/ml, sodium chloride 3 to 10 mg/ml and apyrogenic water with pH making within 6.0 to 7.5.

EFFECT: preparation has a direct antiviral effect, suppresses reproductive ability of viruses.

2 cl, 3 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to RSV replication inhibitors of formula (I) or salts thereof or stereochemically isomeric forms, where R is a radical of formula (a) or (b) . Q is hydrogen or C1-6alkyl substituted with a heterocycle selected from oxazolidine, morpholinyl and hexahydrooxazepine. Alk denotes C1-6alkanediyl. X is O; -a1=a2-a3=a4 - is -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH- or -CH=CH-CH=N-; R1 is selected from optionally substituted pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrrolyl. R2 is C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, Ar-C1-6alkyloxyC1-6alkyl, C3-7cycloalkyl, Ar-C1-6alkyl. R3 is cyano. Ar is phenyl o substituted phenyl. The invention also relates to pharmaceutical compositions containing compounds (I) and a method of producing compounds (I).

EFFECT: high efficiency of the compositions.

9 cl, 20 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared invention refers to chemical-pharmaceutical industry, and concerns pharmaceutical compositions effective particularly in treating motor fluctuations taking L-dopa for treating Parkinson's disease and containing a subacid material representing edible acid or a combination of edible acids providing the pH value of the composition within 5.5-6.5 and a pharmacologically effective amount of micronised L-dopa as an active ingredient in which the active ingredient is found as particles on a surface of larger particles of the carrier.

EFFECT: preparation of new pharmaceutical compositions for treating Parkinson's disease.

38 cl, 4 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutical medications, in particular, to anti-helminth medications based on therapeutic vegetable raw material. Anti-helminth medication, made in accordance with the claimed invention, contains extract of absinthe usual or wormwood, powder of tansy flowers, powder of clove buds, extract of milk thistle, powder of ginger root and powder of garlic with defined component ratio.

EFFECT: medication extends spectrum of therapeutic-preventive impacts on organism and increases patient convenience during treatment course.

5 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method of treating hypertension, congestive cardiac failure, stenocardia, myocardial infarction, atherosclerosis, stroke. A method of treating involves introduction to a patient requiring such treatment of the solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in which the active ingredient makes more than 46 wt % of total weight of the oral dosage form. The oral dosage form is presented in the form of a tablet or a film-coated tablet and produced by methods other than wet granulation with excipients by means of water and/or a water solution of a binding agent.

EFFECT: realisation of the specified purpose.

12 cl, 2 ex

Material // 2437650

FIELD: chemistry.

SUBSTANCE: granular material contains (a) at least 50 wt %, in terms of the weight of granular material, of a solid water-insoluble inorganic mixed compound of layered double hydroxides of metals capable of binding phosphate, and which contains iron (III) and at least one of the following metals: magnesium, calcium, lanthanum or cerium; (b) 3-10 wt % chemically bound water in terms of the weight of granular material; (c) not more than 47 wt % filler in terms of the weight of granular material. The granular material is obtained via wet granulation. The disclosed granular material is meant for use in therapy for a condition or disease associated with unfavourable content of phosphate in the body.

EFFECT: invention enables to maintain physical integrity of granules and batches during storage, good phosphate binding after ingestion of the granules without their excessive breakdown in the mouth.

22 cl, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmacy, namely an antituberculous composition. The pharmaceutical composition contains sodium salt of para-aminosalicylic acid, zinc sulphate, lactose, polyvinylpyrrolidone, citric acid, stearic acid salt, carboxymethyl sodium starch, colloidal silicon dioxide and polyethylene glycol.

EFFECT: composition is characterised by high therapeutic activity, satisfactory technical characteristics and shelf life 2 years and more.

11 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: oral composition contains 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid or its salt, polyvinylpyrrolidone and an alkaline compound, solution 5 % wt/vl of which has pH 10 or more. The preferential alkaline compound is L-arginine of potassium carbonate or sodium hydroxide. The oral composition can be presented in the form of a solid form or in the form of a water solution.

EFFECT: oral composition under the invention exhibits the improved gastrointestinal absorption and keeps stable solubility even with gastrointestinal pH variations.

10 cl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, namely preparation of a pharmaceutical and similar product. The product contains a number of ingredients having active substances delivered in an integrated delivery device, or a carrier.

EFFECT: product provides selective release speed control of each active substance delivered in the same product.

24 cl, 99 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and can be applied for treatment of type 2 diabetes mellitus. Composition containa as active substances N-(β-oxyethyl)-4,6-dimethyldihydropyrimedone-2 (xymedon) and inulin in ratio (2.5-5):(1-3). Composition can additionally contain magnesium, zinc, chromium asparaginates and can be made in form of capsules or pills.

EFFECT: effect from application of pharmaceutical composition for treatment of type 2 diabetes mellitus consists in continuous reduction of glucose level in blood and normalisation of lipid metabolism parameters.

13 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compositions of quinolinone derivatives, methods of obtaining and application of such compositions. Pharmaceutical composition contains lactate of compound 4-amino-5-fluorine-3-[6-(4-methylliperazine-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-one, or its tautomer or their mixture, in quantity from 10 to 80 wt % and at least one ingredient, selected from group, which includes (I) cellulose; (II) silicon dioxide; (III) magnesium stearate and (IV) ingredient, selected from crospovidone, starch and lactose. Composition is included in composition of capsule or pill.

EFFECT: compositions according to invention demonstrate satisfactory properties relating to rates of solution and stability.

49 cl, 2 dwg, 21 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, and deals with medical form and method for delivery of medical substances, in particular, dependence habit-forming medical substances, which are characterised by stability to solvent extraction, compression, crushing and milling.

EFFECT: ensuring initial fast release of medicinal substance with following continuous period of controlled release of medicinal substance.

42 cl, 9 ex, 34 tbl, 22 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly immunology, namely immunocorrection drugs, and can be used as an inducer of a granulocyte-macrophage colony-forming factor in cells of a mononuclear phagocyte system in vitro and for efferent therapy in pathological conditions accompanied by decrease in cell-mediated immunity. The drug represents oxidised dextrane of average molecular weight 35 - 65 kDa. The drug can be presented in the form of a solution or a nanoliposomal emulsion of the concentration of oxidised dextrane 1-5 wt %. The drug is applied by introduction in a cell culture of the mononuclear phagocyte system in an amount containing oxidised dextrane 125-250 mcg per culture medium 1 ml.

EFFECT: drug under the invention exhibits high biocompatibility.

8 cl, 1 tbl, 4 ex

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