Composition for peroral or rectal usage

FIELD: chemical-pharmaceutical industry.

SUBSTANCE: it has been suggested to apply a solid composition for manufacturing a pharmaceutical tablet or a suppository, its melting point being 25°C or higher and it contains an uninterrupted lipid component that contains either one or more than one galactolipids, one or more glyceride ether of fatty acids, possibly one or several out of the following: water and mono-triatomic alcohol at the quantity being up to 15 weight% against the weight of composition, and one or more agent chosen among pharmacologically active agent. The method for manufacturing the composition mentioned includes mixing galactolipids and glyceride ethers of fatty acids followed by dissolving pharmacologically active agents in a liquid phase, cooling up to a solid state and forming a tablet or a filled capsule. Pharmaceutical tablet or suppository are depicted that include uninterrupted lipid phase possibly containing an inert nucleus and, also, food tablets or suppositories of similar composition that include food agents instead of pharmacologically active agent and, possibly, having got one or more submembranes consisting of food excipients. The innovation provides economy and increased comfort in usage.

EFFECT: higher efficiency.

42 cl, 13 ex, 10 tbl

 

The SCOPE of the INVENTION

The present invention relates to a pharmaceutical composition tablet and suppository for oral or rectal introduction on the basis of lipid materials vehicles, and to methods of its production and injection.

PRIOR art

From the point of view of convenience for the patient and technology of the most attractive pharmaceutical form for oral administration of pharmaceutical agents is a tablet, and in some cases may be preferred rectal administration via suppository. However, not all pharmaceutical agents can be easily prepared in the form of tablets or suppositories. In particular, this is true of many active principles, which are poorly absorbed from the gastrointestinal tract, therefore, for optimal suction required to deliver them in a pharmaceutical carrier containing lipids that cannot be compounded in the form of tablets or suppositories. Instead they have to use capsules with hard or soft shell. However, the preferred material of the shell gelatin is often insufficient inert pharmaceutical excipients of this type and limits the shelf life of the drug in capsule form, or require the use of hard gelatin capsules. Hard gelatin ka is Sula, however, it is very uncomfortable to swallow. In recent years among consumers there have also been concerns about the gelatin of animal origin.

On the other hand, oral administration of pharmaceutical agents in the native lipid based, placed in capsules, undoubtedly increases the effectiveness of the medicinal product in terms of bioavailability. Examples are compounds such as cyclosporine and saquinavir, sold under the name Sandimmum Neoral®, Novartis, and Invirase®Roche, respectively. Such media on a lipid basis are either oily liquids such as micro-emulsions or dispersions, such as emulsions or liposomal preparations, which are difficult to include in tablets.

In numerous publications describe the use of lipids as the excipients of the tablets in combination with non-lipid components. Description of prior art in the field of drugs in tablet form are listed in the "Modern Pharmaceutics" (Editors G. Banker and C.Rhodes, Marcel Dekker Inc., New York 1996, Chapter 10, pp.33-394). Most tablets are made by compressing the powder. Pharmaceutical(s) agent(you) is mixed with excipients to obtain a free flowing powder. Among the traditionally used excipients are those that can be classified as lipids such as glycerol triacetate, beginat gli is Wendy Erin, palmitostearate glycerin, zinc stearate, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and waxes. Other lipophilic ingredients include waxes and light mineral oil. Use synthetic lipophilic and amphiphilic ingredients, such as polyethylene glycol (PEG), polyoxyethylenesorbitan, sodium lauryl sulfate and monolaurin sucrose.

Most of the above-mentioned lipid ingredients act as soluble or insoluble lubricants. They are combined with other ingredients such as fillers (e.g. lactose and starch), binders (e.g. starch adhesive and leavening agents (e.g., microcrystalline cellulose and cross-linked polyvinylpyrrolidone). In addition to their application as lubricants, lipid ingredients used in drug controlled release.

In WO 95/20945 disclosed the preparation of lipophilic carrier in the form of an oily liquid or a dispersion having a continuous lipid phase containing non-polar lipid in combination with a polar lipid material and, possibly, a polar solvent, and the polar lipid material is galactolipid material consisting of at least 50% of digalactosyldiacylglycerols and the rest on the other polar lipids.

In WO 92/05771 disclosed forming lipid particle matrix containing biologically active(s) material(s)that contain(s) at least two lipid component, and one non-polar and the other amphipatic and polar. In contact with the aqueous solvent this matrix spontaneously forms a discrete lipid particles. It is believed that amphipatic and polar components of the lipid matrix of the form a bilayer, and are selected from phospholipids, such as phosphatidylcholine; nonpolar lipids represent a mono-, di - or triglycerides.

TASKS INVENTIONS

One task of the present invention is to create a composition for solid pharmaceutical or dietary pill or suppository, which possesses the useful properties of lipids as pharmaceutical carriers for absorption in the gastrointestinal tract and/or sustained release, and/or facilities, and/or savings. (Under the food pill implied tablet supplements.)

Another objective of the invention is to create a composition corresponding media pharmacologically active or nutritional agents.

Another objective of the invention is to develop ways of making the above compositions and include pharmacologically active agent or food in the specified composition of the media.

An additional is the tasks of the present invention is obviously derived from the following brief description of the invention, description of the preferred embodiments and the accompanying claims.

BRIEF description of the INVENTION

In accordance with the present invention is disclosed a composition for solid pharmaceutical or food pills, which has a melting point of from 25 to 50° (C or above, preferably from 30 to 45°S, more preferably from 33 to 42°containing a continuous lipid phase containing a polar lipid component, preferably consisting of a polar lipid component, non-polar lipid component and a pharmacologically active agent. The polar lipid component consists of one or more polar lipids. Nonpolar component consists of one or more non-polar lipids. One or more polar lipids are membrane lipids, including glycolipids and phospholipids. One or more non-polar lipids preferably represent glycerides, i.e. glycerol esters of fatty acids (mono-, di - and triglycerides). The source of all polar and nonpolar lipids according to the invention can serve as food products or materials of food varieties. Polar lipids according to the invention are amphiphilic lipids such terminal groups as galactose or phosphate esters. The polar lipid component according to the invention together with a non-polar lipid com what onetom in different ratios, to ensure the controlled inclusion of a drug, including food additives, agents. It is believed that the mechanism of inclusion based on the interactions of the polar end groups and lipophilic chains of the nonpolar component to enable connection. Pharmacologically (including in terms of food replenishment) effective composition for a given pharmacologically active agent or mixture of agents can be determined experimentally by varying the ratio of polar and non-polar components. Pharmacological or food efficiency to some extent also affected the composition of polar and non-polar component.

Preferably the polar component of the composition according to the invention contains, or more preferably consists of one or more polar lipids from vegetable source, such as oat grain or soybeans. Preferably non-polar lipid component of the composition according to the invention contains, or more preferably consists of one or more glycerides of vegetable source, such as stone fruits, palm oil, coconut oil, palm oil and cottonseed oil.

Especially preferred composition for solid pharmaceutical or dietary pill or suppository according to the invention contains lipid material only races who sustained fashion of origin.

According to the present invention also disclosed a solid tablet, made of the above-mentioned pharmaceutical or food composition, in particular by extrusion, molding or casting.

According to the present invention also disclosed a suppository made of the above-mentioned pharmaceutical composition, in particular by extrusion, molding or casting.

In the pharmaceutical literature continuous lipid phase is described as oily liquid that must be input in the form of oral liquids or enclose in a capsule with a hard or soft shell. However, such oily liquid not included in the scope of the present invention. Also known lipid phase in the form of dispersions, i.e. dispersed aqueous solvents. Lipid emulsions and liposomal preparations are examples of such dispersions, which by definition do not represent a continuous lipid phase and therefore not included in the scope of the present invention.

Polar component according to the invention may be described as formed from the membrane(s) of the lipid(s), i.e. the lipid components of biological membranes. Membrane lipids contain polar, hydrophilic end group and one or more lipophilic hydrocarbon chains. This combination makes the molecules of membrane lipid amphipod the ical and gives the possibility to combine them with water, and oils. Such membrane lipids can be classified according to their chemical structure, which depends on how the polar end group is associated lipophilic chains. Two main groups - sphingolipids (associated with sphingosine) and glycerolipid (glycerin). Depending on the characteristics of the polar end groups of sphingolipids and glycerolipids can be further classified as phospholipids with end group representing a phosphate ester, or glycolipids with terminal group, representing a carbohydrate. Depending on the specific nature of the carbohydrate groups of the membrane lipids is sometimes referred to as, for example, galactolipids, which are glycerolipid with galactose in a polar end group. The well-known examples of membrane lipids include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and digalactosyl-diacylglycerol (DGDG). Membrane lipids can be extracted, for example, from egg yolk (egg lecithin), milk and dairy products, soybeans (soy lecithin), other oilseeds, grains of oats and other cereals and grains. These extracts can be further processed so that they become such as PC from soybeans and galactolipids oat grains. Preferred polar lipids are galactal pity, in particular, the galactolipids oat grains (CPL-Galactolipid) or from soybeans (soya lecithin or soy PC). Especially preferred are partially hydrolyzed galactolipids.

Synthetic polar lipids and analogues of membrane lipids, based on the carbohydrate group or a phosphate ester group, included in the concept of polar lipid component according to the invention.

Preferred non-polar lipids according to the invention are complex glycerol esters of fatty Calotte esters include mono-, di - and triglycerides. Edible oils are triglyceride oils, which can be obtained mono - and diglycerides. Other non-polar lipids according to the invention include vegetable and animal oils of different origin, synthetic oils, fatty acids, natural and synthetic glycerides, esters of Sterol, fatty alcohols. Synthetic non-polar lipids and analogues of fatty acids are also covered by the invention. Description of polar and nonpolar lipids are listed in the "Fatty Acid and Lipid Chemistry" (Frank Gunstone, 1996, Blackie Academic &Professional, Chapman & Hall).

Triglycerides can be selected from the stone palm oil or natural oils with similar relatively high content of solid fat or melting interval. Preferred non-polar lipids include faction is Ostashkovo palm oil, received industrial fractionation stone palm oil in particular mixtures of triglycerides, such as stone fruits, palm stearin based on the combination of mainly lauric, myristic and palmitic esters of glycerol. Preferred monoglycerides are monoglycerides derived from edible oils, in particular monoglycerides with medium chain length (chain length With8-C10derived from coconut oil, monoglycerides with normal chain length (chain length With16-C18derived from most vegetable oils.

In accordance with a preferred aspect of this invention a continuous lipid phase may contain up to 15 wt.%, preferably up to 10 wt.%, most preferably up to 5 wt.% water and/or alcohol, including alcahol or triol, such as ethanol, 1,2-propylene glycol, low molecular weight polyethylene glycol and glycerin.

Continuous lipid phase, by definition, cannot contain water or alcohol in excess of the number that is compatible with its property of being continuous.

According to the invention also disclosed a pharmaceutical composition or food or suppozitornyj carrier comprising a continuous lipid phase having a melting point of from 25 to 50° (C or above, preferably from 30 to 45° S, more preferably from 33 to 42°containing, preferably essentially consisting of a polar lipid component in combination with non-polar lipid component.

According to the present invention also disclosed a method of manufacturing a pharmaceutical composition or dietary pill or suppository having a melting point of from 25 to 50° (C or above, preferably from 30 to 45°S, more preferably from 33 to 42°containing a continuous lipid phase containing, preferably consisting of a polar lipid component, non-polar lipid component and pharmacologically active chemical or nutritional agent, in which the polar lipid component are mixed with non-polar lipid component at the first temperature at which at least one of these components is in a liquid state, to form a liquid continuous lipid phase, in this liquid continuous lipid phase dissolve one or more of these agents, cool the resulting solution or aliquot to a second temperature at which it solidifies, with the specified second temperature is in the range from 25 to 50° (C or above, preferably from 30 to 45°S, more preferably from 33 to 42°C. Cooling may lead to the formation of the cake, if it is avodat in a large volume, or powder, if the liquid product is loaded into the injector, preferably at a temperature slightly above its melting point and sprayed, for example, on a cooled metal surface, in particular a polished chrome surface of the stainless steel belt, moving the rollers. The powdered product can also be obtained by spraying a liquid product into the atmosphere with a temperature below the temperature of solidification of liquid product. The cake can be turned into powder by, for example, crushing at low temperature.

In accordance with a second preferred aspect of the disclosed tablet or suppository according to the invention, coated(th) one or more layers of coating excipients, respectively, tablet or suppository, therefore, to provide a pill or suppository enteric coating and/or shell, physically stabilizing the tablet or suppository at a temperature of its melting point or above, and the appropriate method of coating shell. Especially preferred is a tablet or a suppository according to the invention with the first or the only shell caused by way of the dry coating sheath, in which the surface of the tablet or suppository mechanical process covering the powder at a temperature at which the tablet and suppository are fairly soft(s), to the powder particles stuck to it (to it) and to give the opportunity to implement them in its surface, but not soft(s) for significant deformation, in particular at a temperature of at 25-10°C below the melting temperature of the tablet or suppository. One or more additional layers can be added to covered so the tablet or suppository standard methods of coating pharmaceutical shell known from the prior art. Tablet or suppository according to the invention can also be molded around the inert core.

Tablet or suppository according to the invention can be made of the pharmaceutical composition or food tablets according to the invention by molding the above-mentioned powdery product, or molding, or any other suitable method. In accordance with a preferred aspect of the invention, the molding is carried out in a form coated with a release agent or a layer of anti-adhesive material, such as amorphous silicon dioxide, corn starch and sodium dodecyl sulfate and poly(perforation), respectively.

The pharmaceutical agent or agents according to the invention can be of any type suitable for the formation of the composition of the tablet or suppository with a pharmaceutical carrier according to the invention, provided that the pharmaceutical agent or AG is, for example, soluble(s) in a pharmaceutical carrier and stable at temperatures above 30° With, preferably above 33°C, most preferably above 40°for a period of time sufficient for inclusion in a pharmaceutical carrier. In this case, "stable" means that not more than 5 wt.% pharmaceutical(s) agent(s), preferably not more than 2 wt.%, most preferably not more than 1 wt.% degraded or lost in the process of inclusion. The term "pharmaceutical agent" includes any substance that prevents, cures or relieves the aberrant state of health, such as nutritional disturbance, in particular a lack of vitamins or failure of essential amino acids, and any substance used for diagnostic purposes, which is administered orally.

The pharmaceutical agent according to the invention can be any of analgesics, anti-inflammatory agents, antihelminthic funds, antiallergic agents, antiarrhythmic agents, antibacterial agents, anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antifungal agents, anti-gout, antihistamines, antihypertensive agents, antimalarial agents, agents antimuskarinovoe act occurs, antimycobacterial agents, antitumor agents, Antiprotozoal agents, antifire innych agents, antiviral agents, anxiolytic agents, agents that block beta-adrenergic receptors, cardiac inotropic agents, corticosteroids, cough suppressant, diagnostic agents, diuretics, dopaminergic agents, enzymes, gastrointestinal agents, hypnotics, hormones of the hypothalamus, immunological agents, immunosuppressive agents, agents regulating lipids, mucolytic funds, muscle relaxants, neuroleptics, food agents, opioid analgesics, parasympathomimetics, hormones of the pituitary, parathyroid agents, prostaglandins, sedatives, sex hormones, sympathomimetics, thyroid agents, vasodilators, vitamins and xantina. Requirements for inclusion of agents, nutritional supplements in tablet according to this invention meet the requirements for pharmacologically active agents.

As an example, it has been unexpectedly discovered that the composition of the solid pharmaceutical or dietary pill or suppository according to the invention can include a wide variety of pharmacologically active or nutritional agents have very different chemical structures, but also increases their absorption in the gastrointestinal tract and/or prolong their effectiveness. The present invention also provides a new paragraph shall be improving and expanding the use of the compositions of tablets for pharmaceutical applications, including the use of nutritional supplements.

Below the invention is explained in more detail by the following examples which do not limit the scope of the invention.

DESCRIPTION of the PREFERRED EMBODIMENTS

Materials. Used lipid materials are listed in Table 1.

Unless otherwise indicated, all percentages in the description of the preferred embodiments are mass percent (wt.%).

Table 1.
Lipid materials
Type of lipidTrade name and source
PL-1The galactolipids oat grains (CPL-Galactolipid; Lipid Technologies Provider AB, Karlshamn, Sweden)
PL-2PC from soybeans (derived from soy lecithin Epikuron 135 F; Lucas Meyer GmbH&Co, Hamburg, Germany)
MG-1The monoglyceride with an average chain length (Akoline MCM; Karlshamns AB, Karlshamn, Sweden)
MG-2Monoglycerides of edible oils (Dimodan LS; Danisco, Copenhagen, Denmark)
TG-1Stone palm stearin (fraction stone palm oil; Karlshamns AB, Karlshamn, Sweden)
TG-2Hydrogenated cottonseed oil (Akofine NF; Karlshamns AB, Karlshamn, Sweden)

PRIMA is 1. An example of manufacturing tablets by compressing a powder mixture of lipids (Method A)

Prepare a mixture of the following ingredients (in g):

Nonpolar lipids (hydrogenated triglycerides; Akofine™)18,00
The polar lipid material (galactolipids; CPL-Galactolipid™)2,00
Vitamin B120,040

The powdered ingredients were mixed in a dry mixer. Aliquots (0.50 g) homogeneous powder was pressed into tablets on a hand press (Manesty Machines Ltd, model # D3). The suppository can be produced in the same manner using an appropriate mold.

EXAMPLE 2. An example of manufacturing tablets by casting the molten mixture of lipids in the form (Method B)

Prepare a mixture of the following ingredients (in g):

Nonpolar lipids (fractionated triglycerides;
stone palm stearin)18,00
The polar lipid material (galactolipids;
CPL-Galactolipid™)2,00
Vitamin B120,040

The ingredients were mixed and the mixture was melted by heating to a temperature of 60°and paramesh the Wali at this temperature for 5 hours to dissolve the vitamin B12. Aliquots (0.50 g) molten phase was moulded, covered with powder hydrogenated triglyceride (Akofine NF™). The form was cooled in the freezer, and the tablets removed. The suppository can be made accordingly using the appropriate form.

EXAMPLE 3. Production of tablets containing vitamin B12, folic acid, retinilpalmitat or desmopressin (in the form of acetate)

Tablets produced in accordance with Method A (as described in Example 1) or Method B (as described in Example 2) using multiple compositions media (table 1) according to the invention. Thus, there was obtained 17 drugs, and their relative effectiveness are shown in Table 2.

The results show that the proportion and structure of the components of the lipid phase affect bioavailability. Observed absorption ranging from strongly increased (5.3 times) to strongly blocked, i.e. almost zero.

Table 2.
Preparations in the form of pharmaceutical/food tablets
Rev. No.MethodActive start/ tablet (0,5 g)Lipids (wt.%)Efficiency (drug comparison = 100)
Vitamin B12 (mg)Polar (wt.%)Non-polar lipid (wt.%)
The glycerides IThe glycerides II
1B120 (PL-1)5 (MG-1)75 (TG-1)33
2B120 (PL-1)10 (MG-1)70 (TG-1)74
3B120 (PL-1)15 (MG-1)65 (TG-1)529
4B120 (PL-1)20 (MG-1)60 (TG-1)191
5B120 (PL-1)30 (MG-1)50 (TG-1)100
6B145 (PL-1)35 (MG-1)20 (TG-1)355
7B157 (PL-1)43 (MG-1)0148
8B110 (PL-1)090 (TG-1)108
9And110 (PL-1)090 (TG-2)6
10B120 (PL-1)15 (MG-2)65 (TG-1)43
11B120 (PL-2)15 (MG-1)65 (TG-1)71
12B120 (PL-2)20 (MG-1)60 (TG-1)0
Folic acid (mg)
13B520 (PL-1)10 (MG-1)70 (TG-1)93
14B520 (PL-1)15 (MG-1)65 (TG-1)117
15B520 (PL-1)20 (MG-1)60 (TG-1)56
16B510 (PL-1)090 (TG-1)81
17And510 (PL-1)090 (TG-2)1
Retinyl-palmitate (mg)
18the 33 (5000 IE)10 (PL-1)090 (TG-1)115
19And33 (5000 IE)10 (PL-1)090 (TG-2)6
Desmopressin* (µg)
20B5020 (PL-1)15 (MG-1)65 (TG-1)**
* In the form of acetate. ** see Example 5

EXAMPLE 4. Testing drugs tablets in healthy people-volunteers

Medicines-tablets, respectively, of vitamin b 12, folic acid and retinilpalmitat tested on healthy people-volunteers. For comparison, each subject was also given the same dose of the active principle in the form of industrial drug-tablets (vitamin B12: Behepan®, Pharmacia; folic acid, Folactin®, Pharmacia; retinilpalmitat, Arovit®Roche). The observed differences in concentration in the blood within a specified period of time expressed as a percentage of the comparison drug, which is taken as 100. Thus, the result above 100 for the compositions according to the invention indicates an increase in the concentration of the active agent in the plasma and, consequently, increase the pharmacologists who eskay efficiency. These tests were conducted with an interval of one week.

Subjects fasted (water intake was allowed) from 22.00 on the day preceding the day of the test. On the day of testing, the subjects arrived at the clinic at 7 : 00. In a vein of the arm inserted intravenous catheter for blood collection. The tablet took about 7 : 30. Took a series of blood samples, as presented in Table 3.

Table 3.
Sampling scheme with blood plasma samples for vitamin B12, folic acid and retinilpalmitat
Time in hours after dosing0,5123468
Connection
Vitamin B12XXXXXX
Folic acidXXXXXXX
RetinilpalmitatXXXXXX

In addition, one sample was collected before dosing. After sampling at 4 hours after administration filed a standard lunch.

Blood samples were processed and analyzed in accordance with GCP (good clinical practice) and recognized analytical methods created by the Laboratory of clinical chemistry, Lund University Hospital, Lund, Sweden, and the Laboratory of clinical chemistry, Huddinge Hospital, Sweden. Concentration in plasma was applied to a schedule based on time. The area under the curve obtained for tablets comparison, taken as 100, and the area under the curve (AUC) for the appropriate tablet according to the invention were expressed as percent of the area under the curve for tablet comparison.

AUC was calculated by the trapezoid to the last concentration in the blood. Except for the drugs No. 13, 14, 15, concentration in samples taken before administration, considered as the source and subtracted from the concentration in the sample taken after the introduction, since before the introduction of the latest products, the samples were not selected; the initial concentration of the active agent in the blood plasma was assumed zero. The results are presented in Tables 2 and 4-6.

# denotes the number of drug (see Table 2).

Table 4.
The concentration of vitamin B12 in si is orode blood (pmol/l)
Time (h)Against.#1#3#10Against.#2#5
0310378300365274258281
14093581130323373319387
2388375861337376290363
3420404893346385353369
4421400807352392354397
6413457787361375330384
8431452710370357355397
Percent against.335294374100

Against.#4 No. 7Against.#6EUR.*#8*
183177169233218279319
239426376262574361382
295375316303473445475
293367341317444446496
311380302317432437495
285366313311412431521
288343311254397443465
Percent against.191148355108

Against.#11 Against.#12
233236271306
354309286284
330350322274
316310313280
316314324252
313241329348
323330337301
Percent against.710
Table 5.
The concentration of folic acid in serum (nmol/l)
Time (h)Against.#13#15Against.#14
0.525132489113
15039919310193
2147504204162208
4525231170273252
812063958697
Percent against.9356117

#17
Time (h)+A55Against.#16
014,82523,7
0,524,88621,7
130142920,7
267947726,2
345333727,2
433831829,8
621615227,6
811710026
Percent against.811
Table 6.
The concentration of retinilpalmitat in serum (micromoles/l)
Time (h)Against.#18#19
00,020,040,03
10,030,070,03
20,040,480,04
30,381,190,05
40,790,920,05
61,831,520,13
80,530.640,12
Percent against. 1156

EXAMPLE 5. Testing drugs-tablet desmopressina (antidiuretic) in healthy people-volunteers

Such a drug-pill tested by measuring the amount of urine produced during a specified period of time, according to the methods described in the literature (Hans Vilhardt and Stefan Lundin, Gen. Pharmac. 17 (1986) 481-483). Healthy male volunteers were starving from 22.00 on the day preceding the day of the test. The next morning, the subject drank the tap water in an amount corresponding to 1.5% based on the weight of his body. Then urine was collected every 15 minutes. The collected amount was measured, and immediately after that, the volunteers drank the same amount of tap water. The pill was taken when the volume of urine collected over a period of 15 min, exceeded 150 ml Light Breakfast was given one hour after the introduction of desmopressina, and a light lunch 3 hours later. Fluid consumed this food included in the drink instead of the collected urine volumes.

The result of this test were expressed as the percentage of cumulated production of urine during reception of tablets of this invention compared with half of industrial tablet comparison, containing 100 µg desmopressina (Minirin®, Ferring), for a period of time of 11 hours, starting 30 min after the injection.

Composition desmopressina according to the invention (Pre the Arat 17) increased antidiuretic effect desmopressina 3.5 times the volume of urine produced over a period of time of 11.5 hours after administration (see Tables 2 and 7).

EXAMPLE 6. Fabrication of coated carbohydrate shell tablet with a continuous lipid phase

Tablets of vitamin b 12 (Example 2; 60 g) were loaded into the drum to cover the shells. At the same time the drum was introduced powdery mixture of 68% Arabian gum, 20% lactose and 12% dextrose (3 wt.% based on the weight of the tablet). A drum with a mixture was rotated at 30 rpm for 3 h at 18°C. the Obtained pellets with a smooth surface can be additionally covered with shells traditional pharmaceutical methods of coating shells, such as coating in a fluidized bed (see, for example: S.C. Porter and C.H. Bruno, Coating of Pharmaceutical Solid-Dosage Forms et al., Eds., 2ndEd. Vol.3, p.71-160, Marcel Dekker, New York and Basel, 1990, cited in this publication literature).

Table 7.
Urine collected after the introduction of desmopressina
Minutes after administrationThe collected urine (ml)
PreparatDrug comparison
30042
4500
6000
75024
9000
10500
12000
15000
180050
210042
24014048
2704660
3003466
3303284
36030120
39018120
42020158
45044206
48070208
51040216
55528322
60042438
64598448
690236432
Accumulated volume8783084

EXAMPLE 7. Production of tablets with a continuous lipid phase containing 1.8 mg of porcine insulin (Method B)

Materials in mass parts:/p>

- non-polar lipids (monoglycerides with medium chain length; MCMG), 180 parts;

- non-polar lipids (fractionated triglycerides; stone palm stearin), 450 parts;

- polar lipid material (galactolipids; CPL-Galactolipid™), 240 parts;

- insulin, 1.8 parts;

- 4% aqueous sodium bicarbonate; 28,2 part.

Porcine insulin (Sigma, no I 5523) was dissolved in sodium bicarbonate solution at 60°C. was Added monoglyceride and the mixture was stirred until the formation of a transparent liquid. Then at the same temperature was added galactolipids and stone fruit palm stearin. Stirring is continued until formation of a transparent liquids. As the cooling fluid, corresponding to the composition of the tablets, hardened; TPL 33°C. Aliquots (500 mg) of the molten composition was moulded, covered with powder hydrogenated triglyceride (Akofine NF™). The form was cooled in the freezer. After curing, the solid tablets were removed manually.

EXAMPLE 8. Commercially available suitable synthetic lipid materials (examples):

Mono - and diglycerides; mono - and diglycerides; mono - and diglycerides; polyglyceryl esters of fatty acids; propylene glycol esters of fatty acids; sorbitane esters of fatty acids; stearylamine sodium and calcium; mono - and diglyceride EPE is s diatsetilvinny acid and diglyceride esters of fatty acids.

EXAMPLE 9: a commercially Available suitable nutritional supplements and other extension materials for inclusion in the composition of the tablets according to the invention (examples):

Amino acids, vitamins and other nutritional agents, in particular lecithin, linseed oil, melatonin. mono-octanol, peptides, in particular di-Decapeptide, Biotin, carnitine, cystine, methionine, isoleucine, leucine, ornithine, lysine acetate, folic acid, vitamin D, cholecalciferol, vitamin E.

EXAMPLE 10. Compositions on the basis of gentamicin sulfate

Were prepared with the following composition according to the invention on the basis of sulfate gentamicin (Gentamicin 2", "Gentamicin 3", "Gentamicin 4") (table 8).

Table 8.
Composition of sulfate gentamicin
Party #Gentamicin sulphateTrack
W 21212-N1 "Gentamicin 1"Gentamicin sulphate party No. C; the amount of experimental party 120 mgGentamicin sulphate 100%
W 20920-N3 "Gentamicin 2"Gentamicin sulphate party No. C; the amount of experimental lots 2×4,75 gGentamicin sulphate 50 mg = 1,05%;

H2O 0.5 g = 10,5%;

Lyso-PC 0.5 g = 10,5%;

CPL-GL 1,05 g = 22,1%

MCMG 1,15 g = 24,2%;

RK stearin 1.5 g = 31,6%
W 20920-N2 "Gentamicin 3"Gentamicin sulphate party No. C; the amount of experimental lots 2×4,75 gGentamicin sulphate 50 mg = 1,05%;

H2O 0.5 g = 10,5%;

CPL-GL1,55 g = 32,6%

MCMG 1,15 g = 24,2%;

P stearin 1.5 g = 31,6%
W 21106-N2 "Gentamicin 4"Gentamicin sulphate party No. C; volume of the experimental batch 4.0 gSulfate gentamicin 120 mg = 3%;

H2O 0.4 g = 10%;

HGL 1.24 g = 31%

MCMG 0,92 g = 23%;

RK stearin 1,32 g = 33%

Abbreviations Table 8: Lyso-PC: lysophosphatidylcholine; HGL: partially hydrolyzed galactolipid (Example 12); MCMG: monoacylglycerol with an average chain length; CPL-GL: CPL-galactolipid; RK stearin: stone palm stearin; P stearin: stearin palm oil.

EXAMPLE 11. Compositions on the basis of vancomycin hydrochloride

Below (table 9) the composition according to the invention on the basis of vancomycin hydrochloride were prepared by filling hard gelatin capsules with the aliquot of liquid compositions at 50°C, followed by cooling and solidification.

Table 9.
Compositions on the basis of vancomycin hydrochloride
Party #Lot size (g)Composition Observations
W 21029-N1 "Vancomycin 1"1,0Hydrochloride vancomycin: 20 mg = 2%;

H2O:0.15 g = 15%;

HGL:0.16 g = 16%

CPL-GL:0.14 g = 14%

MCMG: 0,22 g = 22%;

RK stearin: 0.31 g = 31%
W 21107-N2 "Vancomycin 2"1,0Hydrochloride vancomycin: 20 mg = 2%;

H2O:0.15 g = 15%;

CPL-GL: 0.31 g = 31%

MCMG: 0,23 g = 23%;

cholesterol: 0.1 g = 10%

RK stearin: 0,19 g = 19%
Significant improvement compared with Vancomycin 1"
W 21209-N3 "Vancomycin 3"6,0Hydrochloride vancomycin: 120 mg = 2%;

H2O:0.9 g = 15%;

CPL-GL: 1.86 g = 31%

MCMG 1,38 g = 23%;

cholesterol: 0.6 g = 10%

RK stearin: 1,14 g = 19%
Approximately 85% of the water can be removed by evaporation at 60°s; improvement compared with Vancomycin 2"
Abbreviations see Table 8

EXAMPLE 12. Preparation of partially hydrolyzed galactolipid (HGL)

The galactolipid (40 g) was dissolved in Meon (2.0 l) using ultrasound. Added water NH3(25%; 10 ml). The mixture was shaken at room temperature for 23 hours, with a yellowish-green color and has a small number of lightly colored precipitate. The solution was evaporated on a rotary evaporator under reduced is the making. Was added 400 ml of acetone for the extraction of fatty acids. After re-evaporation at 60°and standing over night supernatant decantation, and the residue was evaporated and dried by freezing after adding water (300 ml). Formed and 31.7 g of gel containing about 12% DGMG (digalactosyl-monoacylglycerides), less than 1% of methyl esters of fatty acids, and about 2% digalactosyl-glycerol. The content of DGDG (digalactosyl-diacylglycerol) decreased, thus, up to about 40%.

EXAMPLE 13. Introduction gentamicin

All experiments used NZW rabbits and all tablets/capsules administered orally. Animals were given four, five or six tablets/capsules, and then water for swallowing tablets/capsules. Animals were deprived of food for approximately 18 hours prior to dose. Blood samples were collected from the ear vein in tubes with sodium citrate before the introduction of dose and 0.5, 1, 2, 6 and in some cases after 3 hours after a dose. The blood samples were centrifuged for 10 min at approximately 2000xg to obtain plasma for the determination of gentamicin EMIT 2000 analysis analyzer Hitachi 704 (table 10).

The area under the curve (AUC) was calculated by the trapezoid to the last concentration in the blood. During the experiment used two different doses (5 or 10 mg/kg body weight). To compare results for different is the courthouse square AUC was divided on the appropriate dose of gentamicin. The resulting concentration in the blood plasma to clean gentamicin took 1. Concentrations in blood Plaza for gentamicin in the presence of three different lipid preparations were expressed as multiples of the factors increasing bioabsorption. So, Gentamicin 2 absorbed 12 times better in comparison with Gentamicin 1 due to the inclusion of gentamicin in the lipid matrix.

Table 10.
The concentration of gentamicin (micrograms/ml) in plasma after oral administration to rabbits
Time after administration (h)Gentamicin 1 (in substance); the dose of 10 mg/kg; n=3Gentamicin 2 (in the lipid matrix); the dose of 5 mg/kg; n=4Gentamicin 3 (in the lipid matrix); the dose of 5 mg/kg; n=4Gentamicin 4 (in the lipid matrix); the dose of 10 mg/kg; n=3
00000
0,50,010,070,090,10
10,010,220,040,07
20,020,110,070,08
3-0,060,06-
40,01/td> 0,060,050,09
60,030,090,060,08
AUC0,090,550,340,48
AUC, converted to put the dose in mg/kg0,0090,110,0680,048
The factor correlation11285

1. Solid composition for the manufacture of pharmaceutical tablets or suppositories, which has a melting point of 25°With or higher, containing a continuous lipid component containing one or more than one galactolipid, one or more than one glycerides ether fatty acids, one or more of the following: water and one trivalent alcohol in amount up to 15 wt.% based on the weight of the composition, and one or more than one agent selected from pharmacologically active agent.

2. The composition according to claim 1, essentially consisting of one or more of galactolipids, one or more glyceridic esters of fatty acids and one or more pharmacologically active agents.

3. The composition according to claim 2, in which at least one of these galactolipids is a partially hydrolyzed galactolipid.

4. Comp the position according to claim 1, in which the specified one or more than one glycerides ether fatty acids are glyceridic ester of fatty acids of vegetable origin.

5. The composition according to claim 4, in which the specified one or more than one glycerides ether fatty acids include triglycerides selected from fractions of stone fruits, palm oil, obtained by industrial fractionation of stone fruit oil palm.

6. The composition according to claim 4, in which the specified one or more than one glycerides ether fatty acids include8-C10monoglycerides and/or C16-C18monoglycerides.

7. The composition according to claim 1, containing water and/or one or more than one trivalent alcohols.

8. The composition according to claim 7, in which the monohydroxy alcohol is an ethanol.

9. The composition according to claim 7, in which diatomic, triatomic alcohol selected from 1,2-propylene glycol, low molecular weight polyethylene glycol, glycerin.

10. The composition according to claim 1, in which the specified pharmacologically active agent selected from analgesics, anti-inflammatory agents, antihelminthic funds, antiallergic agents, antiarrhythmic agents, antibacterial agents, anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antifungal agents, anti-gout, antihis the amine funds antihypertensive agents, antimalarial agents, agents antimuskarinovoe act occurs, antimycobacterial agents, antitumor agents, Antiprotozoal agents, antithyroid agents, antiviral agents, anxiolytic agents, agents that block beta-adrenergic receptors, cardiac inotropic agents, corticosteroids, cough suppressant, diagnostic agents, diuretics, dopaminergic agents, enzymes, gastrointestinal agents, hypnotics, hormones of the hypothalamus, immunological agents, immunosuppressive agents, agents regulating lipids, mucolytic funds, muscle relaxants, neuroleptics, opioid analgesics, parasympathomimetics, hormones of the pituitary, parathyroid agents, prostaglandins, sedatives, sex hormones, sympathomimetics, thyroid agents, vasodilators, vitamins and xantina.

11. The composition according to claim 1, containing up to 10 wt.% water.

12. The composition according to claim 11, containing up to 5 wt.% water.

13. Solid composition for the manufacture of food tablet or suppository, which has a melting point of 25°With or higher, containing a continuous lipid component containing one or more than one galactolipid, one or more than one glycerides ether fatty acids, possibly one the or more of the following: water and one trivalent alcohol in amount up to 15 wt.% based on the weight of the composition, and one or more than one agent selected from food agents.

14. The composition according to item 13, essentially consisting of one or more of galactolipids, one or more glyceridic esters of fatty acids and one or more nutritional agents.

15. The composition according to 14, in which at least one of these galactolipids is a partially hydrolyzed galactolipid.

16. The composition according to item 13, in which the specified one or more than one glycerides ether fatty acids are glyceridic ester of fatty acids of vegetable origin.

17. The composition according to item 16, in which the specified one or more than one glycerides ether fatty acids include triglycerides selected from fractions of stone fruits, palm oil, obtained by industrial fractionation of stone fruit oil palm.

18. The composition according to item 16, in which the specified one or more glyceride esters of fatty acids include C8-C10monoglycerides and/or C16-C18monoglycerides.

19. The composition according to item 13, containing water and/or one or more than one trivalent alcohols.

20. The composition according to claim 19, in which the monohydroxy alcohol is an ethanol.

21. The composition according to claim 19, in which diatomic, triatomic alcohol selected from 1,2-propylene glycol, low molecular weight polyethylene glycol, glycerin.

22. To notice indicated in paragraph 13 containing up to 10 wt.% water.

23. The composition according to item 22, containing up to 5 wt.% water.

24. A method of manufacturing a pharmaceutical composition or dietary pill, which has a melting point of 25°and above, in which

one or more of galactolipids, mixed with one or more glyceride esters of fatty acids at the first temperature at which at least one of these components is in a liquid state,

in the liquid continuous lipid phase is dissolved one or more pharmacologically active agents,

the solution of these one or more pharmacologically active agents or nutritional agents, or part of them in the lipid phase is cooled to a second temperature at which it solidifies,

formed into tablets by stage cooling aliquot of the solution or from the main mass of the product obtained at stage cooling, or

form filled capsules, preferably hard gelatin capsules, by conducting stage cooling aliquot of the solution, which were filled with these capsules.

25. The method according to paragraph 24, wherein the specified first temperature is 25°C and above.

26. The method according to paragraph 24 or 25, where the specified solution is cooled completely, at which the formation of p is doskoobraznaya product from the specified main mass of the product.

27. The method according to paragraph 24 or 25, wherein the specified solution is fed to the nozzle and is sprayed on the surface or in a cavity with a temperature below the melting temperature of the liquid, resulting in a powdery product.

28. A method of manufacturing a pharmaceutical or dietary pill or suppository, in which powdered product p or 27 is pressed into a pill or suppository.

29. The method according to p, wherein before pressing the plug(s) and/or the mold for pressing tablets or suppositories are covered with a release agent.

30. The method according to clause 29, where the release agent is selected from stearic acid or its salts.

31. The method according to p, in which cooling is carried out by casting aliquots of the specified solution in the mold, resulting in a molded tablet or suppository.

32. The method according to p, where the casting mold is covered with a release agent.

33. The method according to any of p-32, wherein the specified tablet or suppository cover one or more powdered pharmaceutical or food excipients.

34. The method according to p, wherein the specified one or more excipients mechanically treated surface tablets so as to form a shell.

35. Pharmaceutical tablet or suppository, essentially consisting the I(s) of continuous lipid phase, may contain inert core, and lipid phase may contain one or more of the following: water and one trivalent alcohol in amount up to 15 wt.% in the calculation of the lipid phase, the composition having a melting point of 25°With or higher and containing one or more polar galactolipids components in combination with one or more glyceride esters of fatty acids, and at least one pharmacologically active agent.

36. Pharmaceutical tablet or suppository, contains(s) the main part, which has a melting point of 25°With or higher, and this the main part consists of a continuous lipid phase and may comprises an inert core, a continuous lipid phase contains one or more galactolipids components, one or more glyceridic esters of fatty acids, the lipid phase may contain one or more of the following: water and one trivalent alcohol in amount up to 15 wt.% based on the weight of the lipid phase, and one or more than one pharmacologically active chemical agent, containing(s) also shell, consisting of a pharmaceutical or food excipients.

37. Tablet or suppository for p, in which(ω) shell includes one or more subblock, consisting of farmacevticheskih or food excipients.

38. Tablet or suppository according to any one of p-37, in which(ω) one or more pharmacologically active agents are selected from analgesics, anti-inflammatory agents, antihelminthic funds, antiallergic agents, antiarrhythmic agents, antibacterial agents, anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antifungal agents, anti-gout, antihistamines, antihypertensive agents, antimalarial agents, agents antimuskarinovoe act occurs, antimycobacterial agents, antitumor agents, Antiprotozoal agents, antithyroid agents, antiviral agents, anxiolytic agents, agents that block beta-adrenergic receptors, cardiac inotropic agents, corticosteroids, means for suppressing cough, diagnostic agents, diuretics, dopaminergic agents, enzymes, gastrointestinal agents, hypnotics, hormones of the hypothalamus, immunological agents, immunosuppressive agents, agents regulating lipids, mucolytic funds, muscle relaxants, neuroleptics, opioid analgesics, parasympathomimetics, hormones of the pituitary, parathyroid agents, prostaglandins, sedatives, sex hormones, sympathomimetics, thyroid agents, aadressiraamat funds vitamins and xantina.

39. Food tablet or suppository, essentially consisting(s) of continuous lipid phase may contain inert core, and lipid phase may contain one or more of the following: water and one trivalent alcohol in amount up to 15 wt.% in the calculation of the lipid phase, the composition having a melting point of 25°With or higher and containing one or more polar galactolipids components in combination with one or more glyceride esters of fatty acids, and at least one food agent.

40. Food tablet or suppository, contains(s) the main part, which has a melting point of 25°With or higher, and this the main part consists of a continuous lipid phase and may comprises an inert core, a continuous lipid phase contains one or more galactolipids components, one or more glyceridic esters of fatty acids, the lipid phase may contain one or more of the following: water and one trivalent alcohol in amount up to 15 wt.% based on the weight of the lipid phase, and one or more than one food agent, containing(s) also shell, consisting of food excipients.

41. Tablet or suppository for p, in which(ω) shell consists of the well or more subblock, consisting of food excipients.

42. The tablet according to any one of p-41, in which one or more than one food agent selected from amino acids and vitamins.



 

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14 cl, 5 tbl, 11 ex

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17 cl, 7 tbl, 7 ex

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8 tbl, 11 ex, 3 dwg

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1 tbl, 3 ex

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3 ex

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4 cl, 4 ex, 1 tbl

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2 ex

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EFFECT: improved and valuable veterinary properties of preparation.

3 tbl

FIELD: veterinary pharmacology, veterinary science.

SUBSTANCE: the suggested method deals with mixing formalin with components followed by heating with subsequent cooling at the following ratio of components including: 0.8%-formalin 5 ml, analgin 1 g, Veratrum tincture 1.0 ml, glycerol 5 ml, citric acid 0.2 g, gelatin 3 g.

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1 ex, 2 tbl

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EFFECT: valuable properties of suppository.

5 tbl

FIELD: chemical-pharmaceutical industry.

SUBSTANCE: the present innovation refers to the area of medicinal preparations, to new thyxotropic butyric carrier, in particular, that contains about 0.2-5 weight% colloid silicon dioxide and about 0.2-5 weight% hydrophilic polymer in edible oil. Interaction between hydrophilic polymer and colloid silicon dioxide in case of their application in the above-mentioned range of concentrations enables to keep low concentration of the last component, but, moreover, provides the chance to obtain solution at sufficient thyxotropy and low viscosity in case of shift. Moreover, the present innovation deals with capsules filled with a thyxotropic carrier and a pharmaceutically active substance.

EFFECT: higher efficiency.

17 cl, 11 ex, 1 tbl

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