Pharmaceutical compositions containing hgh for oral administration

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, and concerns a pharmaceutical composition for treating hGH deficiency in the form of a solid oral dosage form which contains human growth hormone (hGH) and N(5-chlorsalicyloyl)-8-aminocaprylic acid (5-CNAC); a method of treating hGH deficiency which involves administering the above pharmaceutical composition into the patient.

EFFECT: group of inventions provides rapid absorption of hGH and good acceptability.

10 cl, 2 ex

 

The background to the present invention

Growth hormone (GH) is a polypeptide hormone which is normally synthesized and secreted somatotropic cells of the anterior pituitary. The secretion of G is strictly regulated by the combination of neural, metabolic, and hormonal factors. Despite the fact that growth hormone is produced throughout the life of the subject, its secretion depends on the age and sex of the subject.

GR binds to a specific receptor on the surface of hepatocytes, fibroblasts and lymphocytes. Known physiological functions of GR seems to be associated with both the direct and indirect effects that are mediated by insulin-like growth factors (IGF). IGF also are peptide hormones, the secretion of which pre-stimulated with the action of GR. IGF include IGF-I and IGF-II. Basically IGF produced in the liver, but can be produced in other peripheral sites.

GR has a significant effect not only on growth but also on body composition and metabolism. Involving IGF GR activates the biosynthesis of proteins by increasing the consumption of amino acids and directly accelerating the transcription and translation of mRNA. In addition, GRS can reduce protein catabolism, mobilizing fat as an efficient energy source. This saves a protein action is s GR is the most important mechanism by which GR accelerates growth and development. In addition, G has an impact on carbohydrate metabolism. Assume that short-term periodic introduction of the GR has insulin-like effects, while GR in excess reduces the utilization of carbohydrates and violates the consumption of glucose in the cells, and thus manifests antiinsulin effect. Assume that the induced GR insulin resistance is associated with postreceptor impaired action of insulin and leads to glucose intolerance, which in turn stimulates the secretion of insulin. During normal development of the GRS and IGF associated with many manifestations of normal growth. The growth hormone deficiency (DR) observed in subjects extremely low Constitution.

Treatment of this resonance has been conducting since 1958 In mind withspecific GR treatment can be carried out using only the human growth hormone (with HGH), which at that time received when cleaning GR only from the pituitary glands of dead people. Due to the limited amount of tissue pituitary person in the world existed with HGH deficiency, and it was used only for the treatment of children with severe stunting. Application of methods of using recombinant DNA allowed us to obtain biosynthetic G, identical with HGH. Clinical trials R is combinatori with HGH (p-with HGH) conducted in 1981, testified about the effectiveness of treatment of children with this resonance with the introduction of R-with HGH. In addition, the presence of p-with HGH allowed to investigate the anabolic activity of the compounds. Modern research suggests that the introduction sverhtehnologichny doses of R-with HGH, there is a positive nitrogen balance, improves protein homeostasis in the body in catabolic States, and accelerated rehabilitation in the treatment of critical conditions in different groups of subjects.

In some cases subcutaneous administration with HGH is associated with difficulties, and also causes local irritation of the skin. The children celebrated the largest number of problems with long-term subcutaneous administration of drugs with HGH. Oral form with HGH meets the requirements of the patient and helps the patient's consent to treatment, because it provides a more acceptable way of delivery in the treatment with the use of peptides.

Recently there have been many attempts to improve the absorption of poly(amino acids), such as peptides and proteins, such as hormones. Basically it is assumed that peptides and proteins must be protected from exposure to the environment of the gastrointestinal tract, which contains many peptidases and there is a significant degradation of peptides and proteins. It is established that the application of Intercollege coverage and EXT is the effect of peptidase inhibitors in the form of pharmaceutical compositions effectively increases the absorption of poly(amino acids), for example, proteins and peptides, when administered orally. However, these approaches alone do not provide adequate protection to achieve a satisfactory level of concentration of the peptide or protein, such as human growth hormone, in the blood plasma.

The literature describes the carriers and compositions suitable for the delivery of active agents, including for delivery of active peptides or proteins. In the application WO 98/34632 A1 as carriers described derivatives of amino acids, suitable for receiving the physical mixtures of biologically active agents. To these compounds is 8-(N-2-hydroxy-5-Chlorobenzyl)aminocaproic acid (compound No. 109). The specified connection is also known as N-(5-chlorosalicylic)-8-aminocaproic acid (in the present description 5CNAC).

In addition, in the application WO 98/34632 A1 describes solutions containing a carrier and a recombinant human growth hormone (example 4). Investigated multiple media, including 5-CNAC (i.e. 8-(N-2-hydroxy-5-Chlorobenzyl)aminocaproic acid, compound No. 109). The connection is included in the composition is intended for insertion into the colon, while the mass ratio of the carrier/growth factor is 25:1. After anesthesia, the rats in the colon dropwise injected composition for VoiceSignal introduction (example 5), after the introduction determine the level of hormone is OST man in the blood.

In the application WO 98/34632 A1 also describe other carriers in the form of solutions for oral administration, which has been studied in models of rats, while the mass ratio of the carrier/growth factor is 200:1.

In the application WO 98/34632 A1 does not provide data about the introduction growth hormone human, and there are no data on the biological activity of the injected growth hormone.

In the application described solid dosage forms for oral administration such as a capsule or tablet.

In the application WO 00/59863 A1 describes disodium salt, monohydrate and the ethanol solvate of some agents for delivery, including N-(5-chlorosalicylic)-8-aminocaproic acid (5-CNAC).

In the application WO 00/59863 A1 are also compositions containing different active agents. The human growth hormone is listed in a long list of active agents, however, are not described specific examples of compositions comprising growth hormone, and there is no data about the introduction of any of the compositions comprising growth hormone. In the compositions containing the preferred active agent, which, as described in the application WO 00/59863 A1 is calcitonin, it is proposed to use the 5-CNAC in the mass ratio of active agent/5-CNAC from about 1:300 to 1:700 (WO 00/59863 A1, p.8).

In the application WO 2005/004900 A1 describes pharmaceutical compositions for oral administration containing the agent to deliver the powdered form. With this 5-CNAC is listed as one of the agents used for delivery. In addition, in the application WO 2005/004900 A1 describes the use of growth hormone as an active agent, but there is no detailed description of the specific combination, and there is no data about the introduction patients with growth hormone. In the application described is only one example of the composition comprising calcitonin salmon and 5-CNAC, in a mass ratio of 1:228.

Despite the fact that in the prior art in General, it is assumed to use the active agents, such as with HGH, in combination with a carrier, such as 5-CNAC, in the literature there are no data to demonstrate that a dosage form for oral administration, containing with HGH, exhibits biological activity, for example, stimulates the production of IGF. In addition, in the prior art indicated that the absorption of the biologically active ingredient, such as human growth hormone, you must use drugs, containing a considerable excess of the media in relation to biologically active ingredient. However, it remains unclear, does the absorbed material biological activity characteristic of human growth hormone, for example, the response is the stimulation of the production of IGF-I.

Despite the proposed delivery options active AG is now (described in the works above), such as peptides and proteins, currently with HGH is still administered by injection. Thus, there is an urgent need for medicines for oral administration, primarily in the form of a solid dosage form for oral administration, such as a capsule or tablet.

Thus, an object of the present invention to provide pharmaceutical compositions suitable for oral administration with HGH.

In addition, it is proposed to use relatively small compared to the active agent, the amount of carrier or agent for delivery, primarily in the composition of the dosage forms containing the human growth hormone in therapeutically effective amounts, e.g., in the amount of 100 mg, the dosage form when the introduction is characterized by several advantages, such dosage forms easier ingested by the patient.

Thus, another object of the present invention are solid dosage forms suitable for oral administration, containing a therapeutically effective amount of human growth hormone.

Despite the fact that 5-CNAC is usually characterized by a rather high tolerance, it is necessary to exclude the introduction of excessive quantities of the specified agent, first of all, during the duration of the compulsory treatment.

Thus, another object of the present invention are available dosage forms containing the human growth hormone that is suitable for oral delivery of active agent and eliminate the impact of a large number of agents for delivery, such as 5-CNAC, on the patient.

Summary of the invention

Thus, the present invention features a pharmaceutical composition that provides effective delivery of human growth hormone (with HGH) to a subject by oral administration.

First of all, the present invention offers a pharmaceutical composition containing as active ingredient the human growth hormone in a mixture of 5-CNAC as agent for delivery, characterized by oral bioavailability, for example, sufficient or optimal oral bioavailability of the active ingredient, such as human growth hormone.

Another object of the present invention features a pharmaceutical composition that contains the human growth hormone (with HGH) and N-(5-chlorosalicylic)-8-aminocaproyl acid (5-CNAC), optionally in the form of a pharmaceutically acceptable salt and/or MES, in a mass ratio with HGH/5-CNAC from 1:0.2 to 1:50 (based on the weight of 5-CNAC in the form of the free acid).

The pharmaceutical compositions according to the present from which bretania, containing human growth hormone, can be used to treat diseases associated with growth hormone deficiency, as well as the conditions under which it is necessary to maintain elevated levels with HGH compared to physiological.

Detailed description of embodiments of the invention

The human growth hormone

The human growth hormone (with HGH or growth hormone or somatotropin) is a polypeptide hormone secretory anterior pituitary gland which stimulates growth of the body, primarily by stimulating the release of somatomedin, and affects the metabolism of proteins, carbohydrates and lipids.

The term with HGH include various natural or synthetic compounds that regulate the growth of animals or plants, such as pituitary growth hormone in vertebrates and auxins in plants. The terms "human growth hormone" or "with HGH"used in this context, means, first of all, human growth hormone, obtained after extraction of the hormone from natural sources and its treatment, as well as derived from recombinant cell cultures. Amino acid sequence and physico-chemical properties with HGH is described, for example, article Gueriguian, etc., Hormone Drugs, U.S.P. Convention, Rockville, MD (1982).

The terms "human growth hormone" or "with HGH also include biologically active equivalents of growth hormone brow the ESA, for example, differing by one or more amino acid residues in the total sequence. Moreover, the term includes variants of GR obtained by replacement, deletion and insertion of amino acid residue in the polypeptide chain, or as a result of posttranslational modifications. There are two options, a natural peptide, containing 191 amino acid residue (somatropin) and the peptide containing 192 amino acid residues and the N-terminal methionine (somatrem), which are usually obtained by recombinant methods.

According to the present invention the preferred form with HGH is a natural peptide that contains 191 amino acid residue (somatropin). Thus, all compounds described in this context, preferably contain somatropin.

Another preferred form of the human growth hormone is a polymer-modified form with HGH, for example, polymer-modified somatropin. The term "polymer modified"means that one or more polymer chains covalently attached to a molecule with HGH, for example, to the molecule of somatropin.

For modification of proteins using various polymer modifiers, above all, water-soluble polymers. PEG (polyethylene glycol) is one of the most widely used polymers for modification of proteins, based on it get the pegylated forms of human growth hormone, for example, pegylated form of somatropin, and found that these forms are characterized by several advantages. Properties and methods of obtaining pegylated active agents, including proteins, such as with HGH, described in the review G. Pasut, etc., Expert. Opin. Ther. Patents, 14(6), str-894 (2004). The specified review included in the present invention by reference.

In a preferred embodiment of the invention in all the compositions described in this context, the use of polymer-modified with HGH is described above primarily with HGH pegylated, such as pegylated growth hormone.

The human growth hormone can be used as lyophilized preparations. Lyophilized preparations with HGH is known in the art, for example, described in the article by M. Pikal, etc., Pharmaceutical Research, Vol.8, No. 4, str-436 (1991) and in the article by M. Pikal and others, Develop. Biol. Standard, t, p.21-38 (1991). These articles included in the present invention by reference.

Agent for delivery

The pharmaceutical compositions of the present invention include as an agent for the delivery of 5-CNAC. The term 5-CNAC, used in this context, means N-(5-chlorosalicylic)-8-aminocaproyl acid. The specified connection is also called 8-(N-2-hydroxy-5-Chlorobenzyl)aminocaproic acid.

5-CNAC is a known connection. The specified connection op is Sano, for example, in the application WO 98/34632 A1 (8-(N-2-hydroxy-5-Chlorobenzyl)aminocaproic acid, compound No. 109).

5-CNAC can be obtained by known methods, for example, as described in the application WO 98/34632 A1. This application is included in the present invention in full by reference.

Property agents for delivery and methods for their preparation are described in detail in the patent US 5773647 and 5866536, these patents are included in the present invention in full by reference.

Usually 5-CNAC used in the compositions of the present invention in the form of pharmaceutically acceptable salts and MES, i.e. in the form of a salt, MES free acid or MES salt. These forms of 5-CNAC include mono - and dioli, for example, monosodium and disodium salts, ethanol-solvate salts and monohydrate salts, and combinations thereof, such as ethanol-solvate of sodium salts and monohydrate sodium salts. Salts containing pharmaceutically acceptable cations, such as potassium, lithium and calcium, are also included in the scope of the invention. Preferably the salt of 5-CNAC means salt of the divalent cation and a divalent anion of 5-CNAC.

In the most preferred versions of the invention, the agent for delivery is the disodium salt of 5-CNAC (5CNAC dss), usually in the form of MES or hydrate. Assumes that all preferred to the munali, described in this context, contain 5-CNAC dss.

It should be understood that the term 5-CNAC dss includes, without limitation, all pharmaceutically acceptable solvate and hydrate, first of all, monohydrate, and hydrates containing various amounts of water. In addition, you can use any solid form, for example, all of the crystalline forms of 5-CNAC dss and their solvate or hydrate.

Salt and/or solvate of 5-CNAC, described above, first of all, disodium salt, as well as receive them as described in the application WO 00/59863 A1, such application is included in this description in full by reference.

5-CNAC and, above all, form a 5-CNAC described above, such as salt, comprising the disodium salt, can be used in the compositions of the present invention in finely ground form.

The most preferred class of pharmaceutical compositions as agent for delivery includes 5-CNAC. 5-CNAC is in free form or in salt form, and may contain particles of various sizes in a wide range, for example, the average particle size is from 50 to 5 μm. Preferably, the agent for delivery is in micronized form. The average particle size of finely agent for delivery, for example 5-CNAC, define, for example, by breaking up large particles of 5-CNAC and periodically comparing the obtained particles with art is startname particles of known size to the formation of particles with the desired average size. The grinding process 5-CNAC as described in the application WO 2005/014031 included in this description by reference, see, for example, p.10 and example 1, which describes obtaining particles of 5-CNAC different size.

The pharmaceutical composition

The pharmaceutical compositions of the present invention can be obtained in the form of capsules including soft gel capsule, tablet, microtablets or other solid dosage forms for oral administration using standard methods known in the art. Capsules and, above all, tablets are the preferred forms.

One object of the present invention features a pharmaceutical composition that contains the human growth hormone (with HGH) and N-(5-chlorosalicylic)-8-aminocaproyl acid (5-CNAC), optionally in the form of a pharmaceutically acceptable salt and/or MES, in a mass ratio with HGH/5-CNAC from 1:0.2 to 1:50, based on the weight of 5-CNAC in the form of the free acid. Preferably the mass ratio is in the range from 1:0.2 to 1:50, especially in the range from 1:0.2 to 1:40. More preferably, the mass ratio is in the range from 1:0.5 to 1:10, in the preferred embodiment, from 1:0.5 to 1:5. The most preferred ratio is the ratio of approximately 1:2.

The absolute amount (mass) of growth hormone in these com is Aziziyah depends on a number of factors, well-known specialist in this field of technology. The amount of pharmaceutically active agent is typically corresponds to an effective amount of the agent that is required to maintain the desired effect, for example, corresponds to therapeutically effective amount.

Typically, the pharmaceutical composition of the present invention in the form of standard dosage forms include with HGH in the amount ranging from 10 mg to 300 mg, preferably in the range of from 50 mg to 200 mg Preferred number with HGH is approximately 100 mg.

The pharmaceutical compositions of the present invention in the form of standard dosage forms typically include 5-CNAC (not necessarily in the form of a pharmaceutically acceptable salt and/or MES) in an amount in the range of 50 mg to 400 mg, preferably in the range of from 100 mg to 300 mg, per weight of 5-CNAC in the form of the free acid. The preferred amount of 5-CNAC is approximately 200 mg, calculated on the weight of 5-CNAC in the form of the free acid.

Suitable quantities with HGH and/or 5-CNAC is possible to determine, for example, by comparing the levels of these agents in the blood plasma after administration of the pharmaceutical compositions of the present invention with similar levels after administration of the known forms for injection, such as commercial with HGH formulations intended for injection, with the account of the recommended dosages.

The total mass of standard dosage forms, such as a capsule or tablet is usually not exceed 1600 mg, preferably do not exceed 1200 mg, more preferably does not exceed 1000 mg, most preferably does not exceed 800 mg

The pharmaceutical composition of the present invention, in addition to with HGH and 5-CNAC, typically includes one or more pharmaceutically suitable of the excipients. Usually these excipients include disintegrity agent, diluent, glidant and/or sizing.

The compositions also can include, without limitation, additives in the standard number, such as compounds to adjust pH, preservative, flavoring agent to mask the taste, flavoring, humidifier, cloud, dye, surfactant, plasticizer, solubilizers agent or any combination thereof. Other additives include phosphate buffer substances, citric acid, glycols, and other dispersing agents.

In a preferred embodiment, the diluent is microcrystalline cellulose, for example, Avicel PH 101 ® (FMC, 1735 Market Street Philadelphia, PA 19103, USA).

In a preferred embodiment, the lubricant is magnesium stearate.

Disintegrity agent selected from the group including any superdisintegrants agent, for example, crospovidone and, above all, povidone. Crosspovidone pre which is a synthetic cross-linked homopolymer of N-vinyl-2-pyrrolidone. Commercial crospovidone include Polyplasdone XL (ISP).

In a preferred embodiment, the pharmaceutical composition, except with HGH, first of all, in dried form, and 5-CNAC, primarily in the form of a disodium salt, includes microcrystalline cellulose, crosspovidone and magnesium stearate.

The pharmaceutical compositions of the present invention can be obtained by standard methods.

To obtain a solid pharmaceutical compositions of the ingredients specified composition in the first stage crushed and, if necessary, receive finely ground particles. Then the processed ingredients suitable ways, for example, stirred mixture of active agent, agent for delivery and other ingredients, you get a homogeneous mass, which is filled capsules, or the stage of filling capsules eliminate, the resulting mass granularit and is used to produce tablets, or the tablets receive direct pressing of the specified mass.

In the present invention are also solid dosage forms for oral administration in the form of powder or granulate. As the dosage forms of the present invention also features suspension, which may be obtained, for example, from the specified powder or granulate.

Solid dosage forms of the present invention for peroral the th introduction of preferably contain intersolubility floor. Intersolubility coatings known in the art. Some known intersolubility coating is obtained on the basis of acrylic resins, such as different brands of products under the trade name Eudragit (company Röhm Pharma Polymers), thus, these known coatings can be used to obtain the above dosage forms. Also known standard methods of analysis in order to assess the sustainability of any of the dosage form to the action of gastric juice, and the ability to dissolve after exposure to the environment of the intestine. You can use the method, for example, described in the Pharmacopoeia of the United States.

Upon receipt of the pharmaceutical compositions according to the invention, it is preferable to use compositions with delayed release, according to the present invention, the most preferred are compositions comprising OROS® or hypromellose (HPMC).

In one variant of the pharmaceutical composition in the form of a suppository. The suppository contains the human growth hormone and 5-CNAC as described above. In addition, suppository contains standard ingredients. These ingredients include different types of PEG, fats, such as purified lard, neutral additives, cocoa butter, cetyl alcohol, glycerides of fatty acids, cutin, etc. In the composition of the suppository and also add hibitory proteases.

Methods of obtaining suppositories known in the art and can be used to obtain suppositories of the present invention.

The use and methods of treatment

The pharmaceutical compositions of the present invention can be used for treatment with HGH deficiency. Thus, the present invention relates to a method of treatment that is that the patient is in need of this treatment is administered a therapeutically effective dose of a pharmaceutical composition as specified in this context. The term introduction means, above all, oral administration oral dosage forms of the present invention. The term patients requiring treatment, includes, first of all, children with stunted growth.

In addition, the invention relates to the use with HGH to obtain a pharmaceutical composition as specified in this context, intended for the treatment with HGH deficiency, for example, in children with growth retardation.

The pharmaceutical compositions of the present invention can also be used to treat patients with Turner syndrome. Thus, the present invention relates to a method of treatment of a patient suffering from Turner syndrome and in need of such treatment, and this method is that a given patient is administered a therapeutically is ffektivnoe dose of the pharmaceutical composition, as indicated in this context. Introduction means, above all, oral administration oral dosage forms of the present invention.

In addition, the invention relates to the use with HGH to obtain a pharmaceutical composition as specified in this context, intended for the treatment of Turner syndrome.

In addition, the pharmaceutical compositions of the present invention can be used to treat patients who need to strengthen the response of IGF-I. Thus, the present invention relates to a method of treating patients, first of all, patients are required to strengthen the response of IGF-I, and this method is that the patient nuzdajusimsja such treatment is administered a therapeutically effective dose of a pharmaceutical composition as specified in this context. Introduction means, above all, oral administration oral dosage forms of the present invention.

In addition, the invention relates to the use with HGH to obtain a pharmaceutical composition as specified in this context, intended to enhance the response of IGF-I.

The pharmaceutical compositions of the present invention can also be used to treat patients who want to enhance the above with HGH physiological value is. Thus, the present invention relates to a method of treating patients, first of all, patients who want to enhance the level with HGH above physiological values, and this method is that the patient in need of such treatment is administered a therapeutically effective dose of a pharmaceutical composition as specified in this context. Introduction means, first of all, the introduction of oral way oral dosage forms of the present invention.

In addition, the invention relates to the use with HGH to obtain a pharmaceutical composition as specified in this context, designed to improve with HGH above physiological values in a patient in need of such treatment.

The pharmaceutical compositions of the present invention can also be used to treat patients in need of such treatment, which you want to restore a positive nitrogen balance and/or to improve protein homeostasis in the body in catabolic States, and/or to accelerate rehabilitation in the treatment of critical conditions. Thus, the present invention includes a method of treatment, which is that the patient in need of such treatment, first of all, the patient, at which you want to restore a positive nitrogen balance and/or is locsite protein homeostasis in the body in catabolic States, and/or speed up the rehabilitation in the treatment of critical conditions, introducing a therapeutically effective dose of the pharmaceutical composition described in this context. Preferred is the introduction of oral way oral dosage forms of the present invention.

In addition, the invention relates to the use with HGH to obtain a pharmaceutical composition, as described in this context is intended to restore a positive nitrogen balance and/or improvement of protein homeostasis in the body in catabolic States, and/or acceleration of rehabilitation in the treatment of critical conditions.

Suitable dose depends, for example, from the subject, the nature and severity of the disease to be treated. Accurate input dose that is effective with high enough, high portability, i.e. safe for the patient, determines therapist. When administered orally, the pharmaceutical compositions of the present invention, the total daily dose with HGH, which can be entered in divided doses, is usually in the range from 10 mg to 2000 mg

Examples

The following examples are presented to illustrate the present invention and are obvious to a person skilled in this field. These examples do not limit the scope of the present invention.

Example 1

In the example described obtaining tablets containing dried with HGH, with rapid release of the active agent. Used lyophilisate contains with HGH (somatropin)/mannitol/glycine/disubstituted phosphate sodium/sodium dihydrophosphate mass ratio 1:2:1:0,3:0,1.

When receiving the pharmaceutical composition used the following ingredients in the specified amounts.

IngredientAmount (mg)
with HGH (lyophilisate)440
5-CNAC dss228
Microcrystalline cellulose80
(Avicel PH 101)
Crosspovidone XL40
Magnesium stearate12
The total mass800

The ingredients were processed according to standard methods. The resulting mixture was pressed into tablets weighing 800 mg

Example 2

Clinical trials

Were testing one drug in phase I involving adult men is a growth hormone deficiency, undergoing treatment with HGH use. A clinical trial was carried out for 2 weeks, during this period, patients were temporarily abolished the standard course of treatment with HGH use. Tests included a stage of washing in one week and treatment of patients within the next week. Within 7 days all patients received daily 4 tablets containing 100 mg of somatropin (one tablet in the morning, one tablet in the evening and two tablets at bedtime). Patients attended medical center 3 times (visits 1-3), once they were in the center within 48 hours and once within 24 hours, Patients were allowed to separate visit 2 and visit 3 (48 h) on two visits to 24 hours For 7 days prior to visit 2, patients were canceled standard treatment with R-with HGH for the entire period of testing. If visits 2 and 3 were divided, some patients also reversed the standard treatment with R-with HGH. The period between visits 2 and 3 shall be not more than 3 days.

Patient characteristics are shown in the table below.

Patients
N=8
Age (years)
The average age of the (CO)48,8(to 8.41)
Median age (range)a 50.5(36-59)
Floor
Male8(100%)
Race
Caucasian8(100%)

Patients
N=8
Weight (kg)
Average weight (FROM)96,43(17,68)
Median weight (range)92,70(74,4-133,5)
WITH mean standard deviation

During the tests was evaluated pharmacokineticist and pharmacodynamic response to the introduction of somatropin, which was evaluated by the level with HGH and IGF-I in serum.

Table
Pharmacokinetic parameters of serum with HGH (AUC0-tand Cmaxgeometric average) for 8 individual patients
The geometric mean valueWashing, day 7Treatment day 1Treatment day 7
AUC0-tCmaxAUC0-tCmaxAUC0-tCmax
Morning0,010,551,382,170,751,32
Evening0,000,280,040,640,010,49
Before going to sleep 0,030,432,002,800,511,09
AUC0-t(μg × h/l), Cmax(ug/l)

After the last dose (day 7 of the treatment period, five patients showed increased AUC0-12and four patients increased levels of Cmaxcompared with the specified parameters at day 7 stage washing. The analysis of concentration with HGH for individual patients suggests that in most patients, somatropin is rapidly absorbed and excreted, usually within 2 hours the System with HGH level in day 1 of treatment period is usually increased compared with day 7 of the treatment period. System level with HGH after the introduction of the evening dose is usually reduced compared to the level after administration of the morning dose and dose, entered before bedtime.

The level of IGF-I on day 7 of the treatment period was increased compared with the level before the introduction of the morning dose, from br135.8 µg/l to 146.3 mg/l (day 1 of treatment period) and to 160,8 µg/l (before the introduction of the evening dose) and up to 150 µg/l (before the introduction of the dose at night). There was a significant difference in levels of IGF-I in different patients. The sub is known 1, 3, 4, 5 and 6 for most measurements was observed to increase the specified level at day 7 of the treatment period compared with the level measured after the stage of washing. Subjects 2 and 8 during the tests, as a rule, there was a decline in the level of IGF-I. the subject 7 was observed increased levels of IGF-I in about half of the measurements, and in other cases there was a decline in the level of IGF-I.

All these 3 patients were observed maxima endogenous with HGH.

During the tests it was established that most patients somatropin rapidly absorbed and rapidly excreted, usually within 2 hours At the system level with HGH on day 1 of treatment period is higher compared to the level in day 7 of the treatment period. System level with HGH after the introduction of the evening dose is usually decreased compared to the level after administration of the morning dose and the dose at bedtime. During treatment with somatropin statistically significant increase of the level of IGF-I on day 7 of the treatment period compared with the level measured at day 7 stage washing. The response of IGF-I was observed in patients who have not identified the endogenous secretion of GR and/or have observed the highest system level GR. Somatropin is characterised by a high tolerance and its introduction was not observed any side effects, although in the tests at imala only 8 patients.

1. Pharmaceutical composition for treatment with HGH deficiency in the form of a solid oral dosage forms, which include human growth hormone (with HGH) and N(5-chlorosalicylic)-8-aminocaproyl acid (5-CNAC) optionally in the form of a pharmaceutically acceptable salt or MES, in a mass ratio with HGH/5-CNAC 1:2 per lot of 5-CNAC in the form of the free acid, where with HGH is in lyophilized form and amount of approximately 10-300 mg

2. The pharmaceutical composition according to claim 1, where with HGH consists of 191 amino acid residue and is characterized by the amino acid sequence corresponding to the natural human growth hormone.

3. The pharmaceutical composition according to claim 1, where 5-CNAC is present in salt form.

4. The pharmaceutical composition according to claim 3, where the salt of 5-CNAC is the disodium salt of (5-CNAC dss).

5. The pharmaceutical composition according to claim 1, in the form of standard dosage forms, including 5-CNAC (not necessarily in the form of a pharmaceutically acceptable salt and/or MES) and optionally one or more pharmaceutically acceptable excipients, where the number with HGH is in the range from 10 mg to 300 mg, preferably in the range of from 50 mg to 200 mg

6. The pharmaceutical composition according to claim 5, where the number with HGH is approximately 100 mg.

7. The pharmaceutical composition according to claim 1, in the form of standard dosage forms, include the her 5-CNAC (not necessarily in the form of a pharmaceutically acceptable salt and/or MES) and optionally one or more pharmaceutically acceptable excipients, where the number of 5-CNAC is in the range of 50 mg to 400 mg, preferably in the range of from 100 mg to 300 mg per weight of 5-CNAC in the form of the free acid.

8. The pharmaceutical composition according to claim 1, where the dosage form is a capsule.

9. The pharmaceutical composition according to claim 1, where the dosage form is a tablet.

10. Treatment with HGH deficiency, which includes an introduction to the patient the pharmaceutical composition according to claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology, particularly to obtaining a modified growth hormone, and can be used in medicine. By recombination, a polypeptide is obtained, which has antagonistic effect on the growth hormone receptor.

EFFECT: invention enables to obtain a polypeptide which is effective when treating conditions caused by excess growth hormone in the body of the patient.

11 cl, 19 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention provides using a prepared compound of a ghrelin splicing version for preparing an effective drug preparation activating body weight and food intake gain and/or stimulating growth hormone release, as well as for treating or preventing cachexia, lipodystrophy and muscle atrophy.

EFFECT: higher clinical effectiveness.

6 cl, 6 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to peptidyl analogues of ghrelin having greater stability which are active with respect to the GHS receptor, having the formula given below: (R2)-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-Rl, where values of A1-A28, R1 and R2 are given in the description, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing an effective amount of said compound, as well as therapeutic and non-therapeutic applications thereof.

EFFECT: high stability.

22 cl, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods for synthesis of nonapeptide ethylamide, having strong LH-RH/FSH-RH activity, of formula pGlu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·2AcOH (I), and intermediate compounds for synthesis thereof. The nonapeptide ethylamide is obtained via condensation of a C-terminal tetrapeptide of formula H-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·HCl (II) with a dipeptide of formula: X-Ser-Tyr-OH (IV), where X is a protective group. The obtained N-substituted hexapeptide ethylamide of formula X-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·HCl (III) is treated with an unblocking agent to remove the N-protective group, and then condensed with a tripeptide of formula pGlu-His-Trp-OH·HCl (V) and the end product is purified through chromatography and extracted in form of a monoacetate salt.

EFFECT: high output.

4 cl, 1 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention refers to the field of pharmaceutical chemistry, and more precisely to a new way of buserelin production with the formula: pGlu-His-Trp-Ser-Tyr-D-Ser(Bu1)-Leu-Arg-Pro-NH-C2H5·2AcOH (I) consisting in the fact that the synthesis is performed by means of condensing of C-ended protected dipeptide with the formula: X-pGlu-His-OH (IIa), where X is a protective group, with N-ended protected heptapeptide with the formula: H-Trp-Ser-Tyr-D-Ser(Bu1)-Leu-Arg-Pro-NH-C2H5 (III) and obtained N-protected nonapeptide ethylamide with the formula: X-pGlu-His-Trp-Ser-Tyr-D-Ser(Bu1)-Leu-Arg-Pro-NH-C2H5 (IV) that is treated with an unblocking agent in order to remove the N-protective group, and the end product is extracted with the help of chromatography.

EFFECT: way of buserelin production.

4 cl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to obstetrics, and concerns treating placental insufficiency in trimester II-III of pregnancy. For this purpose, conventional therapy is complemented with oxygen therapy and foetal sex determination. Those pregnant women with a predicted female foetuses require therapeutic inhalations with mixed gas containing oxygen - 40%, atmospheric air - the rest at air flow 5-6 litres per minute, length of a session 30 min once a day, the therapeutic course 10 procedures, while those pregnant women carrying female foetuses require therapeutic inhalations with mixed gas containing oxygen - 60%, atmospheric air - the rest at air flow 5-6 litres per minute, length of a session 45 min once a day, the therapeutic course 15 procedures.

EFFECT: method provides effective treatment of placental insufficiency with reduced side effects ensured by dosed oxygen therapy shown by foetus sex determination test.

2 ex

Ghrelin analogues // 2427587

FIELD: medicine.

SUBSTANCE: invention relates to peptide analogues of formulae (I) and (II): (R2R3)- A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21A22-A23-A24-A25-A26-A27-A28-R1 in which A1-A28 and R2-R3 are defined in the description for each of the formulae (I) and (II), pharmaceutically acceptable salts thereof and pharmaceutical compositions containing an effective amount of formula (I) compounds and which can be used in the method of suppressing growth hormone secretion and a method of screening a compound which is capable of binding with the GHS receptor.

EFFECT: high efficiency of using the composition.

31 cl, 5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, in which X is or ; Y is H; Z is -C(O)-; R1 and R3 each independently denotes H or (C1-C4) alkyl; R2 and R4 each independently denotes , , or ; R5 denotes H or (C1-C6) alkyl; R8 and R9 each independently denote (C1-C6) alkyl; and Q is H.

EFFECT: possibility of use in stimulating the growth hormone in a subject based on the said compounds.

49 cl, 2 tbl, 57 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to administration of formula (I) described new triazole derivatives as greline-like ligands of growth hormone secretion stimulating receptors (GHSS receptors) that can be effective in treatment or prevention of GHSS receptors mediated physiological and/or pathophysiological conditions in mammals, preferentially in humans. Formula (I): where R1 is chosen from a group including hydrogen atom, (C1-C12)alkyl phenyl, naphthyl, (C5-C14)phenyl(C1-C12)alkyl, indolylalkyl which can contain up to 3 substitutes independently chosen from a group including halogen, -F, -CI, -Br, -I, -NO2, (C1-C12)alkyl, phenyl, naphthyl, -O-(C1-C12)alkyl; R2 is chosen from a group including (C1-C12)alkyl, phenyl, naphthyl, (C5-C14)phenyl (C1-C12)alkyl, indolylalkyl which can contain up to 3 substitutes independently chosen from a group including halogen, -F, -Cl, -Br, -I, -NO2, (C1-C12)alkyl, phenyl, naphthyl, -O-(C1-C12)alkyl; one of radicals R3 and R4 represents hydrogen atom, and other radical are chosen from a group including hydrogen atom, phenyl, naphthyl, indolylalkyl; R5 is chosen from a group including hydrogen atom, phenyl, naphthyl, -CO-(C3-C8)cycloalkyl, -CO-phenyl, -CO-(C5-C7)heteroaryl containing 1, 2 nitrogen atoms, -CO-(C3-C7)heteroaryl(C1-C4)alkyl containing 1, 2 nitrogen atoms, -CO-(C5-C6)heterocyclyl containing 1, 2 nitrogen or oxygen atoms, -CO-C*(R9R10)-NH2, -CO-CH2-C*(R9R10)-NH2, -CO-C*(R9R10)-CH2-NH2, phenylsulfonyl which can contain up to 3 substitutes independently chosen from a group including halogen, -F, -CI, -Br, -I, -N3, -CN, -NR7R8, -OH, -NO2, (C1-C4)alkyl; R6 represents hydrogen atom; R7 and R8 represent hydrogen atom; R9 and R10 are independently chosen from a group including hydrogen atom and (C1-C4)alkyl; m relates to 0, 1 or 2, and preferentially 0; and * means carbon atom in a R or S configurations, if it is chiralene.

EFFECT: invention refers to GHSS receptors antagonists and agonists which can be used for modulation of these receptors and are effective in treatment of said conditions, particularly growth impairment, cachexia, short-term, intermediate and/or long-term energy balance control; short-term, intermediate and/or long-term food intake control (stimulation and/or suppression); adipogenesis, adiposity and/or obesity; body weight growth and/or reduction in mammals.

22 cl, 6 tbl, 15 ex, 46 dwg

FIELD: chemistry; biochemistry.

SUBSTANCE: proposed are human growth hormone conjugates, obtained by removing a hydrogen atom from -NH2 in the Gln side chain which is formed from the human growth hormone or a human growth hormone compound.

EFFECT: design of an efficient method of producing human growth hormone conjugates.

6 cl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for preparing a medicinal agent containing vardenafil hydrochloride trihydrate in the solid form wherein vardenafil hydrochloride trihydrate is treated with suitable pharmaceutical additives at temperature from approximately 20°C to approximately 45°C. The ambient relative humidity of the procedure makes 30% to 90%. The treated medicinal agent is film-coated at temperature within the range from 40°C to 55°C.

EFFECT: method according to the invention provide the additional stage of repeated hydration for the purpose of preparing the trihydrate form of vardenafil hydrochloride.

20 cl, 3 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes new pharmaceutical compositions of (2R,3R,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-fluor-2-isobutylryloxymethyl-4-methyl-tetrahydrofurane-3-yl ester of isooleic acid and hydroxypropyl cellulose. The composition contains 50 to 95 wt % of the above active agent, 1 to 4 wt % of hydroxypropyl cellulose and at least one excipient in the amount up to 49 wt %.

EFFECT: compositions according to the invention provide high bulk density, low granule size, more applicable for better compactibility, flowability and improved solubility profiles.

21 cl, 8 dwg, 11 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is disclosed is a pharmaceutical formulation containing an active agent stabilising an amorphous form of imatinib mesylate, and amorphous imatinib mesylate. The active agent is selected from solid dispersions, and dry co-milling products with excipients. The solid dispersion contains an additional excipient selected from cellulose derivatives, polyvinylpyrrolidone, polyethylene glycols of various molecular weight, polyethylene/polypropylene/polyethylene oxide block copolymers, and polymethacrylates. The excipients for dry co-milling selected from polyvinylpyrrolidone, cellulose derivatives, alkaline earth silicates, and silicon dioxide.

EFFECT: active agents stabilise imatinib mesylate in the amorphous form.

3 cl, 4 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: group of invention refers to medicine, and aims at apoptosis induction in Jurkat cancer cells. What is declared is using donor carbon monoxide CORM-2 for apoptosis induction in Jurkat cancer cells. The method involves Jurkat cancer cell culture in a complete nutrient medium. Thereafter, CORM-2 is added in the final concentration of 50 mcM and exposed for 24 h in the 5% CO2 environment at temperature 37°C.

EFFECT: group of inventions enables the effective apoptosis induction and may be used for treating oncological diseases.

1 dwg, 3 tbl, 1 ex, 2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition the form of an oral suspension consisting of valsartan or a pharmaceutically acceptable salt thereof and at least one or two or more ingredients specified in glycerol or a syrup or a mixture thereof, a preserving agent, a buffer system, a suspending/stabilising agent and anti-foaming agent. The buffer system is specified in sodium citrate, potassium citrate, sodium bicarbonate, sodium dihydrophosphate and potassium dihydrophosphate, and maintains pH of the composition within the range of 3.0 to 5.0. Further, the present invention refers to using the pharmaceutical composition for preparing a drug.

EFFECT: orally administered valsartan suspension provides high bioavailability and reduced variability of response to the administered dose when administered to different subjects or one subject.

10 cl, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: modified release pharmaceutical composition of bupropion hydrobromide contains a core with a therapeutically effective amount of bupropion hydrobromide and a controlled release polymeric coating. The coating contains a water-insoluble polymer in an amount of 1 wt % to 12 wt % of tablet weight and a water-soluble polymer in an amount of 1.5 wt % to 10 wt % of weight tablet. The above coating surrounds the core at least partially. The composition releases bupropion hydrobromide in a dissolution medium containing 0.1N HCl and 5%-40 vol % of ethanol at a rate of approximately 1.1 or less than a release rate of bupropion hydrobromide from a modified-release similar pharmaceutical composition in a dissolution medium containing 0,1N HCl, measured over the range of time at least from 0 to 2 hours by means of type I USP apparatus at 75 rpm and at 37 ±5°C.

EFFECT: invention provides a reduction in the alcohol-caused dose fall (drop) of bupropion hydrobromide.

9 cl, 55 dwg, 46 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutical compositions for treating or preventing C. difficile infection in an individual. The composition is presented in the form of a solid dosage form and contains a therapeutically effective amount in tiacumicine, a stabilising amount of one or more antioxidants, such as butylated hydroxytoluene, and optionally one or more pharmaceutically acceptable excipients. The invention also refers to a method of treating C. difficile associated diarrhea using the given composition.

EFFECT: compositions of the invention have a high stability and a long shelf life.

14 cl, 5 dwg, 4 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns a pharmaceutical composition for treating skin diseases. The composition contains a combination of methylprednisolone aceponate and glycoceramides and a glycoceramide complex containing cholesterol in the amount of 1-3%, and phospholipids in the amount of 25-34%, and excipients. A method for preparing the composition consists in the fact that methylprednisolone aceponate is introduced into an emulsion base containing the glycoceramide complex in the form of a solution to form a coagulation structure.

EFFECT: new pharmaceutical composition is characterised by a wide spectrum of pharmacological properties, stability, uniform distribution of the active ingredients.

9 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely, to antidiabetic composition. Method of obtaining antidiabetic pharmaceutical composition includes preparation of trituracio mixture of active substance repaglinide, taken in therapeutically efficient quantity, with complex-forming substance, solubiliser and colloid silicon dioxide, further addition of filling agent, disintegrant and lubricant, and tabletting by method of direct pressing.

EFFECT: pharmaceutical composition in form of tablet, obtained by claimed method, is characterised by high degree of active substance release, satisfactory strength and has storage term longer than 2 years.

10 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to gel composition for nasal introduction of neurotransmitters. Composition includes, at least, one neurotransmitter, for instance, such as dopamine; at least, one lipophilic or partially lipophilic carrier; and compound or mixture of compounds, possessing activity with respect to reduction of superficial tension, in amount, efficient for formation of emulsion in situ when composition contacts water.

EFFECT: composition ensures high bioactivity and bioavailability of neurotransmitter in plasma and brain.

14 cl, 3 dwg, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: microparticle contains an agglomerate of particles containing a hydrophilic active substance, wherein the particle contains an amphiphilic polymer composed of a hydrophobic segment of polyhydroxy acid and a hydrophilic segment of polysaccharide or polyethylene glycol, and a hydrophilic active substance. What is also disclosed is a method of producing the agglomerated microparticles, which involves (a) a stage of preparing a reverse phase emulsion, (b) a stage of preparing a solid residue containing the hydrophilic active substance, and (c) a stage of introducing the solid residue into a liquid phase containing a surface modifier.

EFFECT: agglomerated microparticles provide the effective encapsulation of the hydrophilic active substance and the release of the hydrophilic active substance at an appropriate speed.

14 cl, 22 dwg, 4 tbl, 31 ex

Up!