RU2190634C2 - Polymeric matrices and their use in pharmaceutical compositions - Google Patents

Abstract

FIELD: polymers, pharmacy. SUBSTANCE: invention relates to specific polymeric matrices poly-(ethylenecarbonates), a method of their synthesis and pharmaceutical compositions based on thereof designated for treatment of chronic inflammatory diseases. Poly-(ethylenecarbonate) is able to a biological decomposition and it comprises links of the formula -(C(O)-O-CH₂-CH₂-O-)- taken in the amount from 70 to 100 mole %, it has an internal viscosity value 0.4-4.0 dl/g measured in chloroform at 20 C and concentration 1 g/dl and vitrification point 15-50 C. Polymer is synthesized by polymerization of ethylene oxide and carbon dioxide in their mole ratio from 1:4 to 1:5 at 10-80 C in the presence of a catalyst synthesized by reaction of diethylzinc and a solvent taken among the group: water, acetone, diol, di- or triphenol. A pharmaceutical composition comprises poly-(ethylenecarbonate) and a pharmaceutically active compound. Polymer shows nonhydrolytic surface erosion in vivo, it is stable for some hours in hot water without significant decrease of molecular mass. Pharmacological compositions can be used for treatment of chronic inflammatory states caused by pathogens, demyelinizing diseases and acute inflammatory states. EFFECT: improved method of synthesis, valuable medicinal properties. 25 cl, 13 dwg, 7 tbl

Description

 The subject of this invention is pharmaceutical compositions containing polymer matrices, in particular compositions containing IL-6, intended for use in the treatment of diseases mediated by IL-1 and / or TNFα, for example, chronic inflammatory conditions. It was shown, however, that the specific polymers of the invention, especially the poly (ethylene carbonate) polymers described below, are more widely used as matrix materials in sustained release formulations containing pharmacologically active compounds, and it has been shown, in particular, that they have a new, unexpected and a very desirable property to undergo non-hydrolytic surface erosion in vivo. Therefore, matrices containing other drugs are also proposed and cited as an example, together with a method for producing polymers and pharmaceutical compositions containing them. In addition, the use of IL-6 for the treatment of conditions mediated by IL-1 and / or TNFα is new and unexpected (previously it was believed that many such conditions are exacerbated by IL-6), therefore, the invention also offers a new use of IL-6 for the treatment of, for example, chronic inflammatory conditions caused by pathogens, demyelinating diseases, and acute and super-acute inflammatory conditions such as septic shock.

Treatment of diseases mediated by IL-1 and / or TNFα
Numerous spontaneously manifested chronic inflammatory conditions have an unknown (possibly autoimmune) etiology, and it is believed that they are mediated by IL-1 and / or TNFα. For example, multiple sclerosis (PC), a crippling nerve disorder characterized by diffuse demyelination plaques in the spinal cord and brain, has attracted the attention of research organizations for many years. Although the exact etiology of multiple sclerosis has not yet been conclusively established, it is believed that it has a strong autoimmune component, as evidenced, for example, by the expanded scope of certain antigens of the main histocompatibility complex of a person in patients suffering from this disease. Current anti-inflammatory drugs, such as ACTH (adrenocorticotropic hormone) or corticosteroids, such as prednisone, seem to accelerate recovery from acute attacks, especially when administered at an early stage, but do not affect the underlying etiology of the disease. Prolonged administration of corticosteroids or immunosuppressants leads to the risk of serious side effects. Recently, it was shown that the recombinant form of IFN-β ₁ reduces short-term plaque formation, but failed to show that it affects the process of long-term development of the disease. The study of the effectiveness of treatment is complicated by the fact that the natural development of the disease manifests itself in the form of alternating spontaneous remission and chronic relapse. In short, despite years of intensive research, there is still no generally accepted specific therapy for this very serious disease.

 Other chronic inflammatory conditions are believed to be induced by external agents, such as pathogens. For example, Lyme disease is a serious chronic condition caused by infection with the tick-borne spirochete Borrelia burgdorferi. After the initial acute stage, characterized by skin lesions and flu-like symptoms, the disease goes into a chronic stage, which can be characterized by arthritis and chronic neuralgic abnormalities. The disease is usually treated with antibiotics and non-steroidal anti-inflammatory drugs, but optimal therapy, in particular for the established disease, has not yet been developed.

 Acute or super-acute uncontrolled inflammatory conditions can also be caused by external causes, such as severe burns or severe infections. For example, septic shock, and in particular adult respiratory distress syndrome (RDSV), is a life-threatening condition for which there is currently no effective treatment. The onset of the disease is rapid, and mortality, as a rule, exceeds 50%. Septic shock is usually the result of a severe bacterial infection and is usually characterized by fever, followed in the later stages by hypothermia, fluctuating blood pressure (hyperdynamic syndrome), followed by hypotension in the later stages, metabolic acidosis, impaired mental ability and extensive organ dysfunction and finally, in many cases ends in death. Most often, septic shock is the result of gram-negative bacterial infection (endotoxic shock), but it can also be the result of gram-positive bacterial infections or other infections. The term "septic shock" used in the text should therefore be interpreted broadly as a term for a shock condition, including RDSV, resulting from a microbial infection, especially a bacterial infection, mainly a gram-negative bacterial infection.

 IL-6 is a known cytokine. It is known that it is used to treat various conditions, such as thrombocytopenia and some cancers. It is usually produced by the body in response to bacterial infections and is involved in mediating inflammation, fever and septic shock. It is a strong immunostimulant, and a number of published data confirm that the mechanisms controlled by IL-6 cause some autoimmune and inflammatory diseases, including systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis, as well as septic shock.

It was a great surprise to discover that IL-6 is suitable for the treatment of chronic inflammatory diseases (not glomerulonephritis), for example multiple sclerosis, and for the treatment of acute and super-acute inflammatory conditions, such as septic shock. The mechanism of its action is unknown, but, without implying any particular theory, we believe that, through a feedback mechanism, IL-6 can inhibit or inhibit the expression, secretion, or functioning of other cytokines, in particular TNFα and / or IL-1, possibly through upregulation isolation of a soluble TNFα receptor antagonist and / or IL-1 receptor, thereby inhibiting the activity of the resulting autoimmune, inflammatory, or shock states, which are mediated mainly by these cytokines. However, it has been shown that in the case of conditions characterized by IL-6 mediated complement-activating antigen-antibody (IgG) complexes, in particular glomerulonephritis (which is usually caused by the accumulation of such complexes in the kidney), IL-6 exacerbates this condition. Thus, we have shown that IL-6 has a healing effect in animal models, for example, for PC and Lyme arthritis, which are believed to be primarily caused by IL-1 and / or TNFα, but exacerbate glomerulonephritis in mice with lupus, which are believed to be directly triggered by IL-6. We have also shown that IL-6 has a therapeutic effect in murine models of endotoxic shock, which, similarly suggest, is mainly caused by IL-1 and / or TNFα.
Therefore, we believe that IL-6 is suitable as an agent for suppressing or inhibiting the expression, isolation or functioning of TNFα and / or IL-1, and especially for the treatment of inflammatory conditions that are not glomerulonephritis, and for the treatment of septic shock. Inflammatory conditions that can be treated with IL-6 include, for example, arthritic conditions, in particular arthritic conditions caused by pathogens, such as Lyme disease arthritis, bacteria-induced arthritis and polyarthritis; multiple sclerosis and other demyelinating conditions (in particular, diseases characterized by demyelination of nerves, brain and / or spinal cord, including, in particular, multiple sclerosis, acute multiple encephalomyelitis or post-infectious encephalitis, optical neuromyelitis, tinnitus, diffuse cerebral sclerosis, disease Schilder, andrenoleukodystrophy, tertiary Lyme disease, tropical spastic parapoiesis and other diseases in which demyelination, especially autoimmune demyelination, is the main symptom ptom); acute acute inflammatory conditions, such as burns, septic shock, meningitis and pneumonia, and autoimmune diseases, including polychondritis, sclerodoma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, pregnant myasthenia, psoriasis, psoriasis arthritis, Steven-Johnson syndrome, myasthenia syndrome, myasthenia , autoimmune inflammatory bowel disease (including, for example, ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, primary biliary cirrhosis of the liver, young man sky diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, and interstitial lung fibrosis.

Thus, according to the invention proposed:
I) Method
inhibiting the expression, isolation or functioning of TNFα and / or IL-1;
treating or preventing an inflammatory condition other than glomerulonephritis;
treating or preventing a condition mediated by IL-1 and / or TNFα;
treating or preventing any of the conditions described above;
treating or preventing a demyelinating disease, in particular multiple sclerosis;
treatment or prevention of an inflammatory condition caused by external causes;
treating or preventing an inflammatory response to a severe acute infection, such as septic shock, meningitis, or pneumonia;
burn treatment;
treating or preventing a chronic pathogen-induced inflammatory condition, for example Lyme disease;
said method comprises administering a therapeutically or prophylactically effective amount of IL-6, for example, an inhibitory TNFα and / or IL-1 amount of IL-6, in particular chIL-6 (in particular, especially when IL-6 is administered as a single a therapeutic or prophylactic agent or possibly administered in combination with antimicrobial or vasoactive agents, in particular not in combination with TNFα agonists or antagonists or with an anti-TNFα antibody), possibly in a slowly released or deposited form, in particular in combination with a dimensional matrix, for example a poly (ethylene carbonate) matrix, described below, to a subject, such as a mammal, in particular a human, if such treatment or prophylaxis is necessary;
II) The use of IL-6, in particular CRIL-6, in the manufacture of a medicament for use in method (I), for example, for the treatment or prophylaxis of any of the conditions listed under (I) above, wherein the medicament may be in a dosage form with prolonged release, may comprise a polymer matrix, in particular a poly (ethylene carbonate) matrix, described hereinafter;
III) The use of IL-6, in particular CRIL-6, for the treatment or prevention of any of the conditions listed in paragraph (I) and
IV) A pharmaceutical composition containing IL-6, in particular chRIL-6, for use according to method (I), for example, for the treatment or prophylaxis of any of the conditions described in paragraph (I) above, possibly in a sustained release form, possibly further comprising a polymer matrix, in particular a poly (ethylene carbonate) matrix, as described below; for example, a sustained release formulation (in particular, a formulation that undergoes biological degradation in vivo over several days, weeks, or months) containing IL-6 in a polymer matrix, for example, in the form of a microparticle or stock, in particular if the polymer exhibits a non-hydrolytic surface in vivo erosion, especially any of the drug administration systems described herein, for use in the treatment of any of the conditions described above, for example, for the treatment of a chronic inflammatory condition.

By IL-6 is meant any compound corresponding to known varieties of interleukin-6 (also known as interferon beta-2 (IFN-β _II ), B-cell stimulant factor 2 (VSF-2), interleukin HP-1 (HR l), hepatocyte stimulating factor (GSF), hybridoma plasmacytoma growth factor (GPRF) and 26kD factor). Recombinant IL-6 is preferred, although non-recombinant IL-6 may also be used, for example, produced by IL-6-secreting cancer cell lines. IL-6 is produced commercially or can be obtained by known methods: EP 220574, 257406, 326120, WO 88/00206, GB 2063882, 2217327, the contents of these sources are included here by reference. IL-6 can be glycosylated, such as produced by eukaryotic cells, in particular CHO cells, or non-glycosylated, such as produced by prokaryotic cells, in particular E. coli. Recombinant human IL-6 (rchIL-6) is preferred, although IL-6 is known to remain active in interspecific transfer, therefore, IL-6, obtained from non-human producers, can also be used and falls within the definition given here of IL- 6. It is believed that proteins having minor variations in the IL-6 sequence, for example, insertions, deletions or mutations of 1, 2, 3 or more amino acids; fusion proteins containing IL-6 and another protein; active fragments of IL-6 and / or other similar variants, processed or mutant forms of IL-6, which have IL-6 activity, fall under the definition of IL-6.

 Acceptable pharmaceutical formulations are known containing IL-6 in conjunction with a pharmaceutically acceptable diluent or carrier. IL-6 can be administered parenterally, for example in the form of an injection or suspension, in particular, according to or similar to the description of Remington's Rharmac. Science, 1980. Suitable carriers include aqueous vehicles such as saline, Ringer's solution, dextrose, Hank's, and non-aqueous vehicles such as fixed oils or ethyl oleate. For normal parenteral administration, IL-6 is suitable in lyophilized form in amounts corresponding to a unit dose that can be mixed with a carrier to form a suitable solution or suspension for injection.

 Alternatively, IL-6 can be administered using an implantable drug delivery system or a drug delivery system with sustained release of the drug, for example, in the form of microparticles or deposited in combination with a polymer to form a polymer matrix, whereby the drug is slowly released from matrices. This is preferable in cases where, for example, the condition to be treated is a chronic, in particular a chronic inflammatory condition, and the required treatment lasts weeks or months. A polymer is understood to mean any suitable (for example, pharmacologically acceptable) linear molecule with a high molecular weight formed from repeating units (including homopolymers, copolymers and heteropolymers), possibly branched or cross-linked, which can be obtained, in particular, by polymerization of a simple molecule or by copolymerizing more than one molecule (for example, obtaining poly (ethylene carbonate) a from ethylene oxide and carbon dioxide, as described below), and possibly containing other units in the polymer chain. Preferably, the polymer is linear and consists of carbon, oxygen and hydrogen, for example poly-DL-lactide-co-glycolide, polyethylene glycol or poly (ethylene carbonate). Preferably, the polymer exhibits non-hydrolytic surface erosion similar to poly (ethylene carbonate) y described below.

 The dosage will vary depending on the exact type of IL-6 used, the recipient, the route of administration and the nature and severity of the condition to be treated. IL-6 is administered to large mammals, such as humans, by subcutaneous injection or in the form of a prolonged release of the drug so as to provide a dose of from 0.5 μg / kg / day to 30 μg / kg / day, preferably from 2.5 μg / kg / day to 10 μg / kg / day or in any other dosage that is safe and effective for in vivo activity in known therapeutic methods of using IL-6, in particular in a dosage that increases platelet count. In the case of severe acute inflammatory conditions, such as septic shock, it is acceptable to administer higher doses intravenously in order to achieve a quick and strong reaction. The frequency of administration of IL-6 can be reduced from daily to administration every other day or every week, or even less in the case of sustained release forms, which are preferred when treatment is carried out for long periods of time. Treatment with IL-6 can lead to fevers, fever, and flu-like symptoms that can normally be cured or prevented by co-administration of non-narcotic analgesics such as aspirin, acetaminophen, or indomethacin. Other serious side effects usually appear only at higher doses, for example above 10 mcg / kg / day, and can usually be eliminated by lowering the dose.

Sustained Release Polymer Matrices
The invention further provides pharmaceutical formulations suitable for sustained release of drugs, which are suitable, for example, for the administration of IL-6, in particular for the indications described above, as well as for the administration of other drugs. Pharmaceutical formulations are mainly those formulations that contain poly (ethylene carbonate) polymers, sometimes referred to as poly (ethylene carbonate) s and PECs.

 Although a number of examples of the use of poly (ethylene carbonate) s in drug administration systems are known from the prior art, they do not describe the specific polymers of the invention and do not describe polymers capable of undergoing non-hydrolytic surface erosion in vivo. The prior art also does not know about such systems for administering a number of specific drugs described here, in particular IL-6, and there is no evidence that a sustained release system is needed to administer such drugs.

 The most unexpected are the decay rates of the polymers of the invention. Based on general chemical concepts, it can be expected that carbonate ester bonds are cleavable in principle. However, it has been suggested that polycarbonates should be stable under moderate in vitro conditions.

 According to Chem. Pharm. Bull. 31 (4), 400-1403 (1983), poly (ethylene carbonate) s disintegrate in vivo, however, the studied polymer was not completely identified, in particular, using modern spectroscopic methods. According to p. 1402, in vivo degradation can only be explained by the action of hydrolytic enzymes.

 According to Chem. Pharm. Bull. 32 (7), 2795-2802 (1984), the microparticles were made from poly (ethylene carbonate) a containing dibucaine. Although the description refers to the achievement originally cited, it turned out that the isolation of dibucaine was not associated with in vitro or in vivo polymer degradation methods, but with diffusion through the polymer. The physical and chemical properties of the investigated poly (ethylene carbonate) as well as have not been sufficiently established.

According to Makromol, Chem. 183, 2085-2092 (1982), mainly p. 2086, suggest that carbon dioxide epoxy polymers are biodegradable and it is noted that preliminary results confirmed the biodegradability of carbon dioxide-ethylene oxide polymers, and hence the possibility of their use in controlled release of drugs. To confirm the statement regarding the possibility of biological decay, Jinko Zoki 3 (Suppl) - - (1974) was referred to. In this publication, it was pointed out that poly (ethylene carbonate) belongs to the group of compounds that are most easily hydrolyzed, and even the pronase enzyme easily destroys them. This means that enzymatic hydrolysis in vitro and in vivo may be possible, since pronase is a mixture of hydrolytic enzymes. However, this statement seems very doubtful. We subjected the poly (ethylene carbonate) s of our invention in the form of compressed discs with a diameter of 5 mm with a weight of 25 mg to 10 mg / ml pronase and 5 mM CaCl ₂ • 2H ₂ O in phosphate buffered saline (PBS) with a pH of 7.4 and 10 mg / ml pronase E and 5 mM CaCl ₂ • 2H ₂ O in phosphate buffered saline solution with pH 7.4 (at 37 ^° C) and no decomposition was observed (see Figure 1). The pronase solution was updated every day.

 It was a surprise to establish the fact that a number of poly (ethylene carbonates) with a certain ethylene carbonate content, viscosity and glass transition temperature range that do not decompose by hydrolysis (for example, in the presence of hydrolytic enzymes, in particular pronase, or under basic conditions), nevertheless disintegrate in vitro and in vivo, namely (and exclusively) due to surface erosion. The expression "surface erosion" is used in the literature, especially with respect to the hydrolytic decomposition of polyanhydrides and polyorthoesters, but it has never been precisely determined.

 Surface erosion occurs if there is mass decay only on the surface of the polymer particles, without reducing the molecular weight of the remaining polymer residue. In those cases where the literature argued that surface erosion was observed, the molecular weight of the residual mass was never determined in parallel with the mass loss determinations, and therefore, in fact, surface erosion never took place.

 In fact, in almost all the polymers ever studied, polymer bulk erosion was observed. Systems subject to polymer bulk erosion have a significant disadvantage in that if the polymer is saturated with a drug compound, for example a peptide that is relatively unstable when exposed to the biological medium into which it will be released, then the drug compound is already in contact with the medium in the bulk part and may lose its activity long before it is released from the polymer. If the polymer experiences surface erosion, in particular in the absence of volumetric erosion, then the introduced drug compound, for example a peptide, will remain protected from the harmful effects of the biological medium until the moment when developing surface erosion reaches the drug particles and the drug particle does not stand out from the surface of the residual polymer mass. In the case of drug delivery systems based on polymer matrices that are prone to surface erosion as opposed to bulk erosion, the drug particle is adversely affected by the biological environment for a short period of time, which provides a longer, stronger and more stable release of the pharmacologically active drug from the polymer matrix.

 For polyanhydrides in recent Proc publications. Nat. Acad Sci. USA 90, 552-556 and 4176-4180 (1993) describe some characteristics of a process similar to surface erosion. However, in these cases, apparently, the entire volume is involved, and molecular weight determinations were not carried out. In addition, such erosion is hydrolytic type erosion. And now it has been found that the selected group of poly (ethylene carbonate) s, described below, shows, both in vitro and in vivo, exclusively non-hydrolytic surface erosion.

The invention provides a polymer that decomposes in vivo and in vitro through surface erosion that occurs by a non-hydrolytic mechanism and having ethylene carbonate units of formula A
- (- C (O) -O-CH ₂ -CH ₂ -O -) -
having an ethylene carbonate content of from 70 to 100 mol%, an internal viscosity of 0.4 to 4.0 dl / g as measured in chloroform at 20 ^{° C.} and a glass transition temperature of 15 to 50 ^° C.

The content of ethylene carbonate in the polymer according to the invention is from 70 to 100 mol.%, In particular 80-100%, preferably from 90 to 99.9%, for example from 94 to 99.9%. The internal viscosity of the polymer is from 0.4 to 4.0 dl / g when measured in chloroform at 20 ^° C. It is preferred that the polymer has an internal viscosity measured at 20 ^{° C.} and a concentration of 1 g / dl in chloroform equal to 0, 4 to 3.0 dl / g.

Its glass transition temperature is from 15 to 50 ^{o C.} , preferably from 18 to 50 ^o C.

The literature describes poly (ethylene carbonate) s having a glass transition temperature of from 5 to 17 ^o C.

The polymers of the invention are preferably prepared by copolymerizing ethylene oxide with carbon dioxide, and the production method is also part of the invention. As a result of the implementation of this preparation method, the polymer contains in most cases, as a co-unit, an ethylene oxide unit of formula B
- (- CH ₂ -CH ₂ -O -) -
If the polymers according to the invention are incubated in an aqueous medium, for example in phosphate buffered saline with a pH of 7.4, the medium practically does not fall into their bulk, as can be seen, for example, from Figure 2. Therefore, no bulk erosion occurs and the remaining mass will remain constant (100%) for a period of time over 28 days, as shown in the right graph of Figure 3.

 Currently, poly-DL-lactide-co-glycolides are the most widely used matrix materials for sustained release drug systems. Such polymers, however, unlike the polymers of the invention, decompose by hydrolysis. For example, mass decay in PBS, as shown on the left side of Figure 3 for one of the most complex types of poly-DL-lactide-co-glycolides, namely glucose-initiated poly-DL-lactide-co-glycolide (DL-PLGLYU), described in GB 2145422.

 The difference during the breakdown between the poly (ethylene carbonates) of the invention and the poly-DL-lactide-co-glycolides (DL-PGL) of the prior art in vivo is shown in FIG. 3. While polylactide-co-glycolides experience volumetric erosion, as evidenced by a decrease in the molecular weight of the residual mass of DL-PLGHLU, the molecular weight of the residual mass of poly (ethylene carbonate) s remains constant (100%).

 The residual mass of the entire implant decreases in vivo in both cases to zero within 1 month, which means that poly (ethylene carbonate) undergoes surface erosion rather than bulk erosion. Due to the absence of bulk erosion, the filled polymer is stored for a long time, for example, until it is introduced, it is impermeable to moisture and stored in the same dry state in which it was obtained. The medicine implanted in it, if it is sensitive to moisture, remains stable.

Однако большинство звеньев этиленоксида в полимерах по изобретению имеют статистически смежные звенья этиленкарбоната, особенно в тех случаях, когда молекулярное соотношение звеньев этиленоксида невелико. Это означает, что в таких случаях большинство результирующих эфирных групп распределено случайным образом между карбонатными группами вдоль полимерной цепи. ¹Н-ЯМР спектры продуктов по изобретению в СDСl₃ подтверждают это предположение. Они дают сигналы при δ= прибл. 4,37 ррm (Пик Iа) звеньев этиленкарбоната (этиленовые звенья между двумя карбонатными группами), при прибл. 4,29 и 3,73 ppm (Пики Iб и Iв) этиленовых звеньев между одной карбонатной и одной эфирной группой и прибл. 3,65 ppm (Пик Iг) этиленовых звеньев между двумя эфирными группами. Затем в пределах точности ЯМР вычисляют долю звеньев этиленкарбоната (А) согласно формуле

В качестве структурной особенности поли(этиленкарбонат)ов в литературе часто вместо содержания в них этиленкарбоната приводят содержание в них эфирных групп. Соотношение эфирных групп (Э) в полимерах по изобретению может быть вычислено по формуле

Согласно WO 92/2260 получают поли(этиленкарбонат)ы, которые содержат звенья этиленоксида и звенья этиленкарбоната в молярном соотношении от 2 до 400: 2, это означает, что полимер содержит по меньшей мере 50 мол.% этиленоксида и менее 50 мол.% звеньев этиленкарбоната. В заявке WO 92/2260 упомянуты биологический распад полимеров и их применение в качестве способных к биологической эрозии матриц для пролонгированного выделения фармакологически активных соединений. Однако не представлено никаких данных о том, что полимеры действительно способны к биологическому распаду. В целом же поли(этиленкарбонат)ы, имеющие такое большое количество эфирных групп, слабо поддаются биологическому распаду. В WO 92/2260 не содержится никаких указаний на возможность поверхностной эрозии полимеров.The invention also provides a method for producing a polymer in which ethylene oxide and CO _{2 are} polymerized in a molar ratio of 1: 4 to 1: 5 in the presence of a catalyst. Obviously, in the framework of this reaction, it is possible to introduce ethylene oxide units into the polymer chain if two epoxy molecules react with each other without the participation of a CO ₂ molecule, for example, if an oxy-anionic intermediate product attacks another ethylene oxide molecule before its carboxylation via CO ₂ . Therefore, it is likely that the polymer contains several units of ethylene oxide. The polymer according to the invention, if it contains ethylene oxide units, has a random distribution of ethylene carbonate and ethylene oxide units according to the total formula A _m —B _n =
- (C (O) -O-CH ₂ -CH ₂ -O -) - _m - (- CH ₂ -CH ₂ -O -) - _n ,
wherein

However, most ethylene oxide units in the polymers of the invention have statistically adjacent ethylene carbonate units, especially when the molecular ratio of the ethylene oxide units is small. This means that in such cases, most of the resulting ether groups are randomly distributed between the carbonate groups along the polymer chain. ¹ H-NMR spectra of the products of the invention in CDCl ₃ confirm this assumption. They give signals at δ = approx. 4.37 ppm (Peak Ia) of ethylene carbonate units (ethylene units between two carbonate groups), with approx. 4.29 and 3.73 ppm (Peaks Ib and Ic) of ethylene units between one carbonate and one ether group and approx. 3.65 ppm (Peak Ig) of ethylene units between two ether groups. Then, within the limits of NMR accuracy, the proportion of ethylene carbonate units (A) is calculated according to the formula

As a structural feature of poly (ethylene carbonate) s, the content of ether groups is often given in the literature instead of the content of ethylene carbonate in them. The ratio of ether groups (E) in the polymers of the invention can be calculated by the formula

According to WO 92/2260, poly (ethylene carbonate) s are obtained which contain ethylene oxide units and ethylene carbonate units in a molar ratio of 2 to 400: 2, which means that the polymer contains at least 50 mol.% Ethylene oxide and less than 50 mol.% Units ethylene carbonate. WO 92/2260 mentions the biological degradation of polymers and their use as biodegradable matrices for the sustained release of pharmacologically active compounds. However, no evidence is presented that the polymers are indeed capable of biodegradation. In general, poly (ethylene carbonate) s having such a large number of ether groups are poorly biodegradable. WO 92/2260 does not indicate any possibility of surface erosion of polymers.

 In examples US 3248415 describe poly (ethylene carbonate) s with a low molecular weight of MB = 700-5000, having less than 70 mol.% Units of ethylene carbonate, different from the polymers of the invention, however, nothing is reported about their biological decomposition.

 According to WO 89/05664, poly (ethylene carbonate) s are described which contain in the described structure II units of ethylene oxide and ethylene carbonate in a molar ratio of 1 to 8: 1, which means that the polymer contains at least 50 mol. % ethylene oxide units and hence at most 50 mol.% ethylene carbonate units, different from the polymers of the invention. Although polymers are described as being applicable to biodegradable drugs, such as implants that may contain a drug compound, no information is provided on surface erosion.

In the method according to the invention, the content of ethylene oxide units, and hence the content of ester groups, which reduces or inhibits the rate of biodegradation of the polymer, is significantly reduced by creating such reaction conditions as the described molar ratio of the reaction components, the reaction temperature, and also by choosing the appropriate catalyst obtained , for example, from Zn (C ₂ H ₅ ) ₂ and water or acetone, or di- or triphenol, in particular phloroglucin, in a molar ratio of 0.9: 1 to 1: 0.9 or 2: 1 to 1: 2 respectively, or pre obtained from Zn (C ₂ H ₅ ) ₂ and diol, especially ethylene glycol, in a molar ratio of from 0.9: 1 to 1: 0.9.

The method is preferably carried out in a solvent or dispersion system of an organic solvent, for example dioxane and CO ₂ . CO _{2 is} preferably administered in liquid form and is present in excess. The pressure is preferably from 20 to 70 bar, and the temperature is preferably from 10 to 80 ^o C, especially from 20 to 70 ^o C.

 Thus obtained polymers according to the invention usually contain less than 15% of the ether groups, preferably less than 10%, in particular less than 5%, for example less than 3%. Poly (ethylene carbonate) s according to the invention, if obtained using a catalyst of ethylene glycol or acetone and diethylzinc, have low polydispersity (MW / Mn), usually less than 5, in particular less than 2.5.

 In the method according to the invention, it is believed that the catalyst or part thereof is a chain initiator of a (co) polymer. When the reaction ends and the chain is completed, the final terminal group is the hydroxyl group. The opposite side of the chain, where the chain began, may be occupied by the catalyst group or its fragment. If the catalyst is obtained from ethylene glycol and diethylzinc or water and diethylzinc, then both ends of the polymer chain are assumed to be identical. However, if the catalyst is prepared from di- or triphenol and diethylzinc, then an aromatic group will be included at the end of the chain where it starts, while the other end of the chain will be a hydroxyl group. Figure 4 shows that the biological decomposition of poly (ethylene carbonate) a, in the event that one of its end groups is blocked, for example, by an aromatic initiator, in particular phloroglucin, proceeds more slowly.

For this reason, it is believed that the decomposition of the polymer chain begins with the terminal hydroxyl group. Alternatively, a later modification of the terminal hydroxyl group can be taken into account, for example, by esterification to block the terminal hydroxyl groups and to regulate the biological degradation of the poly (ethylene carbonate) s according to the invention. Suitable terminal ether groups are biocompatible ether groups like fatty acid ester groups (C ₁ - ₄₈ ), preferably (C ₁ - ₃₀ ), especially fatty acid ester groups (C ₁ - ₁₈ ), for example, ester groups of acetic acid and stearic acid or an ester group of carbonic acid, in particular an ethylene carbonate group, or an ester group of pamoic acid or an ester group of lactic or glycolic, or polylactic, or polyglycolic, or polylactic-co-glycolic acid.

Poly (ethylene carbonate) s according to the invention are stable for several hours in hot water (90-100 ^o C) without a significant reduction in molecular weight. A significant increase in the glass transition temperature, for example up to about 18 ^{° C.} or 20 ^{° C.} , is observed after being kept in boiling bidistilled water for 5 hours. By carrying out this reaction step, a polymer of higher purity is obtained. We found that polymers treated in this way are better processed.

The poly (ethylene carbonate) part of the polymers according to the invention is, as already mentioned, non-hydrolyzable, therefore they are stable for at least 1 month when exposed to hydrolytic enzymes under physiological conditions or water at pH 12 and 37 ^o C (see Figure 1 and 8). However, it was found that the polymers of the invention disintegrate in vivo and in vitro by surface erosion under the influence of the anion of the superoxide radical O ₂ ^- . Anions of the superoxide radical O ₂ ^{- are} produced in inflammatory cells in vivo and ex vivo in the presence of poly (ethylene carbonates) according to the invention, as can be seen from FIG. 5. Polylactide-co-glycolides, the most widely used matrix materials for sustained drug release systems today, which decompose by volume hydrolysis, do not induce the production of superoxide radical anions O ₂ ^- , which is shown in the same figure for glucose-initiated poly-DL- lactide-co-glycolide, which was used for FIG. 3.

In vitro, an aqueous system was created containing potassium superoxide as a source of O ₂ ^- and exhibiting surface erosion of the poly (ethylene carbonate) s of the invention (see FIG. 8). In vitro, pH 12 was chosen, since the O ₂ radical ^is quite stable at this pH.

 It is interesting that poly (propylene carbonate), which differs from poly (ethylene carbonate) by replacing hydrogen of an ethylene unit with a methyl group, is generally not capable of biological decomposition.

 Using suspensions of microparticles of poly (ethylene carbonate) s according to the invention, a toxicological study was conducted on 48 rats for 21 days and on 24 dogs for 35 days. Each introduction was made two introductions on the 1st and 17th day. After subcutaneous and intramuscular administration of 10 and 40 mg of polymer microparticles / kg of body weight, neither clinical symptoms of systemic toxicity nor corresponding effects on hematological parameters, on clinical blood parameters, on body weight and on food intake were observed. The injection sites were tested for histopathological changes 4 and 21 days after administration in rats and 18 and 35 days after administration in dogs. In addition to the expected inflammatory response, no unusual histopathological changes were detected.

Polymer disintegration time according to the invention can be adjusted within wide limits, depending on their molecular weight, ethylene oxide content, the identity of the terminal groups, eg biocompatible ester groups, and the presence of O ₂ ^- radical neutralizers such as vitamin C, and may last from 6 days to 6 months and longer, in particular up to 1 year. The radical converter may preferably be incorporated into the polymer as an additive.

 The molecular weight of the MB (co) polymers of the invention is from 80,000, preferably from 100,000, in particular from 200,000 to 2,000,000 Daltons, as determined by gel permeation chromatography with methylene chloride as eluent and polystyrene as a reference.

 In Chem. Pharm. Bull. 32 (7), 2795-2802 (1984), discussed previously, mention that poly (ethylene carbonate) s having a molecular weight of 50,000 to 150,000 Daltons were used. We found that in vitro and in vivo polymer degradation can only take place sufficiently if the molecular weight is more than 80,000, preferably more than 100,000 (Figure 6); this is a preferred aspect of the invention.

The polymers of the invention can be used in pharmaceutical formulations, especially as matrix materials for the binding of pharmacologically active compounds. Since volume erosion is not observed under in vivo and in vitro conditions and the active compound is protected by the polymer, the active compound is released as soon as (but not earlier) it appears on the matrix surface due to surface erosion of the matrix. In an in vitro aqueous system of pH 7.4 containing no O ₂ ^- , only trace amounts of the active compound were released (see FIG. 9).

 Another advantage of surface erosion is that the molecule size of the pharmacologically active compound does not affect the rate of release.

 Thus, the invention provides a pharmaceutical composition of a pharmacologically active compound in a polymer capable of non-hydrolytic surface erosion, especially with a linear, namely 1: 1 linear correlation of the release of the active compound and non-hydrolytic degradation of the polymer mass and the protection of the active compound in the polymer matrix.

 The compositions are preferably used in the form of microparticles or implants.

 The preparation of the pharmaceutical forms according to the invention can be carried out by methods known per se, microparticles — by appropriate air drying or emulsification methods, implants — by mixing the drug compound and poly (ethylene carbonates) in the form of solid particles at higher temperatures, at which the poly (ethylene carbonate) become soft and easy to process, possibly followed by cooling the mixture to a solid state and giving it a suitable shape. It is also possible to mix the drug compound in a dissolved or dispersed state with a solution of poly (ethylene carbonate) and then evaporate the solvent, after which a solid residue is formed into convenient implantable forms.

 Pharmaceutical formulations containing microparticles can be prepared by treating them with appropriate galenic excipients and passing them through appropriate metering devices.

 Depending on the properties of the drug and the production method, the content of the drug administered can vary widely, from about 0.001 to about 70%, in particular from 0.001 to 20%, preferably from 0.001 to 5% by weight. The penetration of the medium into the polymer due to the high drug loading should be avoided and the upper load contents should be limited.

 In medical practice, the administration of drug compounds can use any type of pharmacologically active compound in combination with the poly (ethylene carbonate) ohm according to the invention. In the case of microparticles, it is preferable to use those types of drug compounds that are pharmacologically active in small amounts and must be maintained constant in the blood for extended periods of time, for example hormones, peptides or proteins, in particular somatostatins, interferons or interleukins, especially those compounds that are unstable and decompose after oral administration in the gastrointestinal system, and parenteral administration thereof is therefore preferred.

 The deposited forms according to the invention can be used to administer various classes of active agents, for example pharmacologically active agents such as contraceptives, sedatives, steroids, sulfonamides, vaccines, vitamins, migraine preparations, enzymes, bronchodilators, cardiovascular drugs, analgesics, antibiotics, antigens , anticonvulsants, anti-inflammatory drugs, drugs against Parkinson's disease, prolactin secretion inhibitors, anti-asthma drugs, geriart of sul and antimalarials. The active agent may be selected from a wide range of chemical compounds, for example lipophilic and / or hydrophilic active agents, including peptides such as octreotide (GB 2234896).

 Active proteins or peptides are preferably cytokines, e.g., interleukins, granulocyte macrophage colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (GM-CSF), or leukemia inhibiting factor, LIF, interferons, erythropoietins, cyclosporins or hormones or their analogues, in particular octreotide.

Pharmaceutical formulations may be used for
immunomodulations when the active ingredient contains a cytokine, for example interleukin (IL-3, IL-6), or stimulation factors for hematopoietic colonies (G-CSP, for example filgrastim, GM-CSF, for example mgramgram, sargramostim, M-CSF), in particular as an adjuvant for vaccines,
restoration of hematopoiesis after myelosuppressive therapy or after a bone marrow transplant, when the active ingredient contains hematopoietic growth factor, for example GM-CSF, G-CSF, IL-3, IL-6, LIF, table cell factor (SCF), or a combination thereof,
creating a high local concentration of the active ingredient, for example, when the active ingredient contains a drug or cytokine, GM-CSF, IL-6, IL-2, IL-4, or a combination thereof to stimulate a protective immune response, for example, when co-administered with irradiated tumor cells or vaccine antigens (analogue of irradiated tumor cells "transfected" with the corresponding cytokine genes),
inducing strong immune responses when the active ingredient contains, for example, GM-CSF, administered in combination with antigens, especially tumor antigens, viral antigens or bacterial antigens,
inducing wound healing by local injection of formulations, for example, when the active ingredient contains GM-CSF,
inducing antigen-specific immune resistance when the active ingredient is, for example, GM-CSF in combination with inhibitors of side molecules (co-receptors), especially inhibitors of CD28-B7 interaction, CD40-CD40 ligand interaction, for adhesion of factor interactions,
concomitant therapy with cytostatic treatment or as a vaccine adjuvant when the active ingredient is, for example, a cytokine, especially interleukin (IL-3, IL-6), or an inducer of cytokine secretion, for example a lipid derivative, in particular the compound described by EP 309411, especially in Example 1, also known as MRL 953,
specific immune suppression, for example, when the active ingredient is an immunophilin-binding immunosuppressant, in particular cyclosporin (e.g. cyclosporin A), ascomycin (e.g. FK506) or rapamycin (e.g. rapamycin or a derivative thereof, as described in WO 94/09010, in particular 40 -O-hydroxyethyl-rapamycin),
treating or preventing autoimmune diseases and inflammatory conditions by slowly releasing anti-inflammatory cytokines, such as IL-6, IL-10 or TGFβ; or interferons, for example INF-β ₁ or betaserone; either soluble cytokine receptors or cytokine receptor antagonists, for example IL-1, TNFα or IL-4,
treating or preventing allergic diseases by slowly isolating a soluble α-chain receptor with high affinity for IgE (Fc _E RI),
treating cancers, for example, with octreotide, cytokines, especially interleukins,
selective treatment, for example for the treatment of leishmaniasis, fungal infections, diseases of the accumulation of enzymes (Tau Sachs, Gauckerillness),
AIDS therapy and ARC,
vaccinations, for example with a tetanus toxin vaccine,
hematopoiesis, for example, when the active ingredient is erythropoietin,
intra-articular administration to inflamed joints when the active ingredient is an anti-inflammatory drug, especially if it is a drug that is not bioavailable when administered orally or has a very short half-life, for example, IL-1β converting enzyme inhibitors, metalloprotease inhibitors.

 Known from WO 94/01133 is a method of enhancing a mammalian immune response to a vaccine, characterized in that it comprises administering to the mammal, if necessary, an effective amount of GM-CSF conjugated to the vaccine. However, the administration of GM-CSF was not a neatly delayed method according to the present invention, which provides an almost constant release of the active compound over a long period of time, whereby the timing of re-administration of GM-CSF can be reduced.

 The invention provides, in particular, the pharmaceutical composition of a pharmacologically active compound in a polymer capable of non-hydrolytic surface erosion, for parenteral administration of interleukin or CSF, in particular in the polymer, as previously described.

 The invention also provides a method of administering such a composition to a subject, which includes administering it parenterally to a subject in need of such treatment.

 The deposited preparations according to the invention can be used according to known indications for a particular drug compound included in them.

 The exact amounts of drug compound or drug to be administered depend on a number of factors, for example, the condition to be treated, the duration of treatment required, the rate of release of the drug compound, and the degradability of the poly (ethylene carbonate).

 The required preparations can be obtained in a known manner.

 The required amount of pharmacologically active agent and its release rate can be determined on the basis of well-known in vivo and in vitro methods, for example, how long the concentration of a specific active agent in the blood plasma remains at the required level. The ability to matrix degradation can also be studied using in vitro and, especially, in vivo methods, for example, by determining the amount of matrix materials in the subcutaneous tissue at certain intervals.

 The deposited preparations of the invention can be administered, for example, in the form of microparticles by oral, nasal or pulmonary, preferably subcutaneous, intramuscular or intravenous administration, mainly in the form of a suspension in a suitable liquid carrier or in the form of implants, for example subcutaneously.

 Re-administration of the deposited preparations according to the invention can be carried out when a sufficiently complete decomposition of the polymer matrix occurs, for example after 1, 2 or 3 weeks or 1 month.

 An advantage of the poly (ethylene carbonate) matrices of the invention is that, during the isolation of the drug compound, the polymer chains break up into small molecular parts that are carried by body fluids from the injection site.

 Examples of drug loads for a preferred octreotide compound are acromegaly in parenteral liquid deposited form having microparticles that contain the peptide in an amount of at least 0.1, preferably 0.5 to 20 percent by weight relative to the (co) polymer matrix, preferably from 2.0 to 10, in particular from 3 to 6% by weight. The total dose of octreotide is from 20 to 30 mg for acromegaly and up to 100-200 mg for brain cancer, in particular, for 1 month of treatment.

 The release time of the peptide from the microparticles can be from 5 days to about 2 weeks or more.

 Conveniently, the sustained-release preparation contains octreotide in a (co) polymer carrier, which, when subcutaneously administered to a rabbit or rat at a dose of 2 mg octreotide per kg body weight of the animal, creates a concentration of octreotide in the blood plasma of at least 0.3 ng / ml and preferably less than 20 ng / ml over an extended period.

The pharmaceutical compositions of the invention may contain additional additives, preferably also incorporated into the (co) polymer, for example a radical scavenger, especially a superoxide radical scavenger O ₂ ^- . The presence of such a neutralizer, for example menadione or vitamin C, reduces the rate of decomposition of poly (ethylene carbonate) a (Fig. 7).

Another type of additive is a hydroxyl radical neutralizer, possibly produced under the influence of the superoxide radical anion O ₂ ^- , for example, a polyol, especially sugar alcohol, in particular mannitol. It was found that this supplement also has a beneficial effect on the increase in body weight of experimental animals that are given microencapsulated IL-3. Without this supplement, weight gain is delayed. When the composition is in the form of microparticles, the same or different additive can be externally attached to existing microparticles, since this has a positive effect on the stability of the suspension of microparticles - against flocculation and sedimentation.

 If there is an additive, then its amount is preferably from 1 to 90% by weight relative to the total weight of the drug.

Significant in vitro and in vivo mass decay under the influence of the superoxide radical anion O ₂ ^- can be seen from Fig. 8. The decay curves for the residual mass are approximately linear and have a different slope, since the decay conditions in vivo and in vitro are different. The amount of decaying mass per unit time is almost constant.

The curves for in vivo release of a pharmacologically active compound, for example human IL-3, under the influence of the superoxide radical anion O ₂ ^- are, like the decay curves, almost linear (Figure 10), which means that the amount of drug release per unit time is also almost constantly.

 The combination of in vivo isolation of human IL-3 and in vivo mass decay is shown in FIG. 11, showing a 1: 1 correlation between in vivo mass decay and drug release.

 EXAMPLES 1-6: General method for the synthesis of poly (ethylene carbonate) s with a catalyst obtained from diethylzinc and water.

 Amounts of reagents, solvent, catalyst, etc. for each experiment are shown in table 1.

200 ml of dry dioxane and 19.5 g (158 mmol) of Zn (C ₂ H ₅ ) ₂ were placed in a 750 ml flask under a nitrogen atmosphere. The flask was equipped with a mechanical stirrer, a dropping funnel, a thermometer and an inlet valve for N ₂ . The dropping funnel was equipped with a CaCl ₂ tube. The solution was cooled to 10 ^{° C.} in an ice bath, and a solution of 2.7 ml of H ₂ O in dioxane was slowly added (see table 1) so that the temperature remained in the range of 10-15 ^° C. The reaction mixture was further stirred for 45 minutes at room temperature until the initially colorless solution turned pale yellow. This catalyst solution was transferred into an autoclave, treated with 40 g of CO ₂ and heated at 125 ^{° C.} for the time indicated in Table 1. Then the mixture was cooled to room temperature and 560 g (12.7 mol) of CO _{2 was} added, followed by 132 g (3 mol) of ethylene oxide for 1 hour. The reaction was carried out for the period of time indicated in table 1. After that, the pressure was reduced for several hours. The product, a sticky suspension, was diluted with dioxane and precipitated by injection of dioxane
solution in 0.25 M aqueous HC1. The precipitate was dissolved in an appropriate amount of CH ₂ Cl ₂ (2-4 liters), washed with aqueous 0.5 M Hcl (2x) and H ₂ O (1x). The solution was dried over anhydrous Na ₂ SO ₄ and evaporated to a final volume of 0.5 to 1.5 liters, depending on the viscosity of the solution. The product was precipitated by pouring a CH ₂ Cl ₂ solution in a 4-fold volume of methanol. The white precipitate was filtered and dried overnight at 0.5 mbar / 50 ^o C. The crude product was reprecipitated from acetone for further purification, see table 2. All products showed identical ¹ H-NMR spectra, except for relative signal intensities at 3, 65, 3.73, 4.29 and 4.37 ppm due to differences in ethylene carbonate content.

All experiments were carried out in a 1.0 liter NB2 autoclave. The molar ratio of H ₂ About: Zn (C ₂ H ₅ ) ₂ = 0.95 for all experiments. The catalyst was pretreated with 40 g of CO ₂ at 125 ^{° C.} for 1 hour, with the exception of Example 1 (10 hours).

 EXAMPLES 7-11: The basic method for the synthesis of poly (ethylene carbonate) s with a catalyst derived from diethylzinc and diol.

 1. Obtaining a catalyst.

200 ml of dry dioxane were placed in a 750 ml dry four-necked flask under a nitrogen atmosphere. 19.50 g (158 mmol) of diethylzinc were added using a glass syringe. The flask was equipped with a mechanical stirrer, a dropping funnel, a thermometer and an argon inlet valve. A dropping funnel was filled with 100 ml of dry dioxane and provided with a tube of calcium chloride. Then the apparatus was placed in a stream of argon. To dioxane was added 9.00 g (145 mmol, 0.92 mol-eq.) Of fresh distilled dry ethylene glycol (stored on molecular sieves) via a dropping funnel under argon flow. The flask was mechanically stirred to 10 ^{° C.} in an ice bath under argon atmosphere. A solution of ethylene glycol in dioxane was added dropwise to a stirred solution of diethylzinc in dioxane over a period of 30 minutes, during which time the temperature was maintained in the range of 10-14 ^° C. The evolution of ethane gas and precipitation were observed simultaneously with the addition of ethylene glycol solution. After the addition was completed, the cooling bath was removed, and the mixture was stirred for an additional 60 minutes, allowing it to warm to room temperature. The heterogeneous mixture was then transferred to an autoclave (1 liter NB2 autoclave) under argon. The autoclave was filled with approximately 40 g (0.9 mol) of carbon dioxide and heated at 125 ^{° C.} for 1 hour with stirring to pre-treat the catalyst with carbon dioxide.

 2. Polymerization.

 The autoclave with the pre-treated catalyst was cooled to room temperature and an additional 560 g (12.7 mol) of carbon dioxide was filled. Then, 132 g (3 mol) of ethylene oxide (99.8%) were added to the autoclaved mixture by slow injection over 1 hour. After the addition was complete, the autoclave was heated to the temperature indicated in Table 3, and the mixture was stirred for the indicated time at this temperature.

 3. Processing.

The autoclave was cooled to room temperature, and the pressure was slowly lowered to atmospheric. The product, a white, sticky suspension, was transferred to 7 L of dichloromethane, 1035 ml of a 0.4 M HCl solution was added, the mixture was stirred for 3 hours at room temperature. The phases were separated, the organic layer was washed twice with 3 liters of 0.5 M Hcl and twice with 4.5 liters of water. The dichloromethane solution was then dried over 120 g of sodium sulfate and concentrated to a final volume of approximately 2 liters. The product was precipitated by slowly adding this solution to 6 liters of methanol. The precipitate was dried for 16 hours in vacuo at 40 ^{° C.} , resulting in a crude polymer, which was then purified as follows.

The crude product was dissolved in dichloromethane, and the solution was poured into a 5-fold volume of acetone for 15 minutes to precipitate the product. The precipitate was dried for 16 hours in vacuum at 40 ^o With the formation of the corresponding poly (ethylene carbonate) a. The physical properties of the products are presented in table 4. All products showed strong IR absorption at 1750 and 1225 cm ^-1 . ¹ H-NMR signal of ethylene carbonate units was recorded at 4.37 ppm.

 EXAMPLE 12: An experimental method for the synthesis of poly (ethylene carbonate) a with a catalyst obtained from diethylzinc and phloroglucinol.

 1. Obtaining a catalyst.

200 ml of dry dioxane was placed in a 750 ml dry four-necked flask under a nitrogen atmosphere. 19.60 g (158.7 mmol) of diethylzinc were added via a glass syringe. The flask was equipped with a mechanical stirrer, a dropping funnel, a thermometer and an argon inlet valve. A dropping funnel was filled with 100 ml of dry dioxane and provided with a tube of calcium chloride. The installation was placed under argon current. Under argon flow, 13.34 g (105.8 mmol, 0.92 mol-equiv.) Of dry phloroglucinol was added to dioxane through a dropping funnel. The flask with mechanical stirring was cooled to 10 ^{° C.} in an ice bath under argon. A solution of phloroglucin in dioxane was added dropwise to a stirred solution of diethylzinc in dioxane over a period of 30 minutes, during which time the temperature was maintained in the range of 10-14 ^° C. The evolution of gaseous ethane and the formation of a precipitate were observed simultaneously with the addition of a solution of phloroglucin. After the addition was completed, the cooling bath was removed, and the mixture was stirred for an additional 30 minutes, allowing it to warm to room temperature. The heterogeneous mixture was then transferred to an autoclave (1 liter NB2 autoclave) under argon. The autoclave was filled with approximately 40 g (0.9 mol) of carbon dioxide and heated for 1 hour at 125 ^{° C.} with stirring to pre-treat the catalyst with carbon dioxide.

 2. Polymerization.

The autoclave with the pre-treated catalyst was cooled to room temperature and an additional 560 g (12.7 mol) of carbon dioxide was filled. Then, 132 g (3 mol) of ethylene oxide (99.8%) were added to the autoclaved mixture by slow injection over 1 hour. After the addition of ethylene oxide was completed, the autoclave was kept under stirring for 260 hours at 21 ^o C.

 3. Processing.

The pressure in the autoclave was slowly reduced to atmospheric pressure. The product was transferred to 4 liters of dichloromethane, 1035 ml of 0.4 M Hcl was added and the resulting mixture was stirred for 3 hours at room temperature. The phases were separated, and the organic layer was washed twice with 1.5 liters of 0.5 M HCl and twice with two liters of water. The dichloromethane solution was then dried over 120 g of sodium sulfate and concentrated to a final volume of approximately 1 liter. The product was precipitated by slowly pouring this solution into 3 liters of methanol. The precipitate was dried for 16 hours in vacuo at 40 ^{° C.} , resulting in a crude polymer, which was further purified as follows.

The crude product was dissolved in dichloromethane, and the resulting solution was poured into a 5-fold volume of acetone for 15 minutes to precipitate the product. The precipitate was again dissolved in dichloromethane, reprecipitated from methanol and dried for 16 hours in vacuum at 40 ^o With obtaining the corresponding poly (ethylene carbonate) a.

Physical properties of the product:
MW = 258000 D, Mn = 35600 D, Tst = 15.4 ^o C.

IR: Strong absorption at 1751 and 1225 cm ^-1 .

According to ¹ H-NMR, the product contains approximately 96% ethylene carbonate.

 EXAMPLE 13: Experimental method for the synthesis of poly (ethylene carbonate) a with a catalyst obtained from diethylzinc and acetone.

132 g (3 mol) of ethylene oxide was copolymerized with 600 g (13.6 mol) of CO ₂ at 50 ^{° C.} for 96 hours in the presence of a catalyst prepared from 8.43 g (145.16 mmol) of acetone and 19.62 g (159 mmol) diethylzinc.

 The preparation of the catalyst and its polymerization was carried out similarly to the process described for examples 7-11, with the exception that acetone was used instead of the diol to obtain the catalyst.

Thus obtained poly (ethylene carbonate) contained 93% ethylene carbonate and had the following properties: MW = 233 kD, Mn = 109 kD, MV / Mn = 2.14, Tst = 22.4 ^o C.

 EXAMPLE 14: Synthesis of terminally stearoylated poly (ethylene carbonate) a.

1 g of poly (ethylene carbonate) a, having Mb = 153000 D, Mn = 68900 D, Tg = 29.1 ^o C, was dissolved in 30 ml of dry dichloromethane. The solution was then treated with 0.98 g (12.38 mmol) of pyridine and 10 g (33.0 mmol) of stearoyl chloride. The reaction mixture was stirred at room temperature for 48 hours, then diluted with 50 ml of dichloromethane and washed successively with 2 x 150 ml of saturated sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate, and the product was precipitated by dropwise infusion of a dichloromethane solution in 300 ml of n-hexane. The resulting crude product was further purified by dissolving in dichloromethane and precipitating from a 3-fold volume of diethyl ether. Finally, the product was dried in vacuo at 40 ^{° C.} for 16 hours, resulting in a poly (ethylene carbonate) terminal stearoylated group.

Mw = 144000 D. Mn = 71000 D, Tst = 25.6 ^o C.

 EXAMPLE 15: Synthesis of terminally acetylated poly (ethylene carbonate) a.

1 g of poly (ethylene carbonate) a (having Mb = 153000 D, Mn = 68900 D, Tst = 29.1 ^o C) was dissolved in 10 ml of dry dichloromethane. 0.98 g (12.38 mmol) of pyridine was added, followed by 10.08 g (98.7 mmol) of acetic anhydride. The reaction mixture was stirred at room temperature for 120 hours. Then it was diluted with 50 ml of dichloromethane and slowly poured into 200 ml of saturated sodium bicarbonate. The mixture was stirred for 30 minutes, and then the layers were separated. The organic was washed again with 150 ml of saturated sodium carbonate, and then with water. The dichloromethane solution was dried over anhydrous sodium sulfate, and the product was precipitated by dropwise infusion of this solution in 300 ml of diethyl ether. The precipitate was again dissolved in dichloromethane and reprecipitated from diethyl ether. The product was dried for 16 hours at 40 ^o C in vacuum to obtain poly (ethylene carbonate) and with the end group, esterified with acetate.

Mw = 150,000 D, Mn = 69100 D, Tst = 26.8 ^o C.

 EXAMPLE 16: Purification of poly (ethylene carbonate) a by treatment with boiling water.

1 g of poly (ethylene carbonate) a (from Example 8, having Mv = 328000 D, Mn = 149000 D, Tst = 16.4 ^o C) was crushed into small pieces and mixed in 50 ml of boiling water for 2 hours. Water was removed and replaced with fresh water, which was again heated to boiling point. After another 3 hours, the polymer pieces were separated and dried in vacuo at 40 ^{° C.} for 16 hours. The resulting product had the following physical properties: MW = 340000 D, Mn = 148000 D, Tst = 28.3 ^o C. Thus, a dramatic increase in the glass transition temperature was observed, which was not associated with a change in the molecular weight of the polymer.

 EXAMPLE 17: Composition (microparticles) with 1% hIL-3 drug filling.

 1. Preparation of microparticles containing the medicine.

1 g of poly (ethylene carbonate) and MB = 328000 D from Example 8 (PEC) was dissolved in 10 ml of methylene chloride with stirring, followed by the addition of 12.1 mg of human interleukin 3 (hIL-3) dissolved in 0.6 ml of water. The mixture was vigorously stirred using Ultra-Turax for one minute at a speed of 20,000 rpm./min (internal W / O phase). 1 g of gelatin A was dissolved in 2000 ml of deionized water at 50 ^o C, the solution was cooled to 20 ^o C (external W-phase). The W / O phase and the W phase were intensively mixed. As a result, the internal W / O phase was dispersed homogeneously in the external W phase as regular droplets. The resulting triple emulsion was slowly stirred for 1 hour. The methylene chloride was evaporated by this, and microparticles were generated and solidified from droplets of the internal phase.

 After sedimentation of the microparticles, the supernatant was aspirated, and the microparticles were regenerated by vacuum filtration or centrifugation and washed with water to remove gelatin. Finally, the microparticles were either freeze dried using mannitol as an agent to increase the volume or dried in a vacuum oven (free mannitol based formulations) for 72 hours and sorted (0.125 mm sieve size) to obtain the final product.

 2. Placebo technology.

1 g PEC Mv = 328000 D from Example 8 was dissolved in 10 ml of methylene chloride with stirring (internal O-phase). 1 g of gelatin A was dissolved in 2000 ml of deionized water at 50 ^o C, and the solution was cooled to 20 ^o C (external W-phase). O and W phases were intensively mixed. Through this, the O phase was homogeneously dispersed as regular droplets in the outer W phase. The resulting emulsion was slowly stirred for 1 hour, and then processed by the method described above.

 EXAMPLES 18-26

All galenic preparations described here were prepared using PECs synthesized according to Example 8 in Table 3, and then purified by a method similar to that described in Example 16. All of them had Mw from 300,000 to 450,000 D, the content of ethylene carbonate was over 94%, and Tg in the range from 18 to 50 ^o C.

 EXAMPLE 18: Compositions (microparticles) having a 0.2% hIL-2 filling.

 2.9 mg of human interleukin 2 (hIL-2) was dissolved in 1.5 ml of water and microparticles containing IL-2 were prepared as described in Example 17.

 The microparticles were freeze dried using mannitol as an agent to increase the volume and sorted (sieve size 0.125 mm) to obtain the final product.

 EXAMPLE 19: Composition (microparticles) having a 0.2% hIL-2 content (anhydrous).

 The preparation was prepared as described in Example 18, but 2.9 mg of human interleukin was dispersed directly in the organic phase (PEC dissolved in methylene chloride).

 EXAMPLE 20: Composition (implants) having a 0.8% hIL-3 content.

 1. Injection molding.

25 mg of microparticles consisting of 100% (w / w) poly (ethylene carbonate) a (placebo), 99% (w / w) poly (ethylene carbonate) a and 1% (w / w) human interleukin-3 or 79 , 2% (w / w) poly (ethylene carbonate) a, 20% (w / w) mannitol and 0.8% (w / w) human interleukin-3, were formed by compression for 3 minutes at 60-70 ^o C and 160 bar in implants (tablets) with a diameter of 5 mm. The tablets were stored at 4 ^{° C.} in sealed glass vials before use for in vitro and in vivo drug isolation experiments.

 2. In vitro drug isolation experiments.

Three mannitol-free tablets, mannitol-containing preparations of human interleukin-3 and placebo preparations were rocked at 37 ^{° C.} in a synthetic culture medium containing 2.5% (v / v) N- [2-hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid] (1 M), 10% (vol./about.) Fetal calf serum and 2% (vol./about.) Penicillin / streptomycin solution. Samples were removed from the medium after 0.5, 1, 2, 5 hours and on 1, 2, 3, 7, 14, 20 days, and the medium was updated. The content of human interleukin-3 in the samples was measured using enzyme-linked immunosorbent assay.

3. In vivo drug isolation experiment
Male rats kept under optimal conditions were anesthetized by drug inhalation and each tablet was implanted in the subcutaneous skin pocket with one tablet of interleukin-3 preparations and a placebo preparation. After 1, 4, 7, 14, 21 days, rats were killed by overdose of narcotic inhalation. The surviving tablets were removed, freed from adherent tissue and dried. The weight loss of the tablets was determined gravimetrically. Then, the content of human interleukin-3 surviving tablets was determined by HPLC and enzyme-linked immunosorbent assay.

 EXAMPLE 21: Composition (w / o / w microparticles) having 0.0002% hIL-2 content.

4 g of PEC was dissolved in 80 ml of methylene chloride using a magnetic stirrer. To this solution was added an appropriate amount of IL-2 (113.2 mg for 2%, 11.32 mg for 0.2%, etc.) dissolved in 6 ml of distilled water or water with a few drops of ethanol. The mixture was vigorously mixed with Ultra-Turax to disperse the IL-2 solution in the polymer phase (internal W / O phase). 1 g of gelatin A was dissolved in 200 ml of 1/15 M phosphate buffer (pH 7.4) at 50 ^° C, the solution was cooled to 20 ^° C (external W phase). W / O and W phases were intensively mixed. As a result, the internal W / O phase was broken into small droplets that were homogeneously dispersed in the external W phase. The resulting triple emulsion was slowly stirred for 1 hour. In this case, methylene chloride evaporated, and microparticles formed from the droplets of the internal phase during solidification.

 After sedimentation (or centrifugation) of the microparticles, the supernatant was aspirated, and the particles were separated by filtration in vacuo and washed with water to remove gelatin. Finally, the microparticles were dried in vacuum for 24 hours and sieved to obtain the final product.

 The encapsulation efficiency determined by HPLC and bioassessment ranged from 10 to 100%.

 EXAMPLE 22: Composition (s / o / w microparticles) having 0.0002% -2% IL-2 content.

 The preparations were prepared as described in Example 21, except that IL-2 was not dissolved in water. Instead of dissolving IL-2, the drug was dispersed directly in the polymer phase (O-phase). The encapsulation efficiency determined by HPLC and bioassessment ranged from 10 to 100%.

 Note: The amount of polymer, methylene chloride, water and drugs vary in a wide range, which did not change the quality of the product. Get a large medicinal filling up to 20%. In the external phase, gelatin is replaced with other emulsifiers, such as polyvinyl alcohol, etc., and / or the concentration of emulsifier / buffer is changed. The described separation and drying processes are replaced with other well-known pharmaceutical technologies, for example, filtration, lyophilization or spray drying.

 EXAMPLE 23: Composition (w / o / w and s / o / w microparticles) having 1% h-GM-CSF filling.

 The preparation was carried out according to the method described in Examples 21 and 22. According to these descriptions, S / O / W and W / O / W compositions are prepared. However, the encapsulation efficiency of W / O / W compositions was 60%, while S / O / W compositions had lower encapsulation efficiencies.

 EXAMPLE 24: Composition (w / o / w and s / o / w microparticles) having from 1 to 10% filling with octreotide pamoate (SMS-PA).

 The preparation was carried out according to the method described in Examples 19 and 20. However, SMS-PA is not a water-soluble substance. Therefore, the drug was not dissolved, but dispersed in water to obtain W / O / W preparations. The encapsulation efficiency, which was determined using GHUR, ranged from 20 to 100%.

 EXAMPLE 25: Composition (w / o / w and s / o / w microparticles) having from 1% to 10% octreotide acetate content.

 The preparation was carried out according to the method described in Examples 21 and 22. The encapsulation efficiency was determined by HPLC, and it ranged from 2 to 40%, which is significantly less compared to lipophilic SMS-PA.

 Higher values were obtained in S / O / W preparations after application of the material of the lyophilized active compound (smaller drug particle).

 EXAMPLE 26: Isolation of octreotide pamoate (SMS-PA) from microparticles in rabbits and implants in rabbits and rats.

 Subcutaneous implantation of poly (ethylene carbonate) disks or injection of microparticles of poly (ethylene carbonate) a (drug replenishment of 1.95%) in an amount of approximately 2 mg of drug substance / kg body weight to male rabbits (hybrid chinchilla, body weight about 3 kg) and subcutaneous implantation of discs in male rats (Wistar, body weight about 375 g). Amounts equal to 40 and respectively 300 mg of the drug-containing polymer in the form of microparticles, respectively compressed as an implant or as a suspension, were administered to each rat or rabbit.

 The implant discs for rats and rabbits had a diameter of 0.5 and 1 cm, respectively, and were made as described in Example 20.

 To determine the release of the drug, blood samples were taken on the 14th and 21st days in rats and rabbits, respectively, and the residual amounts of the drug in the implants were measured using radioimmunoassay and HPLC.

 A linear correlation of the mass loss of poly (ethylene carbonate) a and the SMS-PA release can be detected (FIG. 13), as demonstrated for hIL-3 with high molecular weight (FIG. 11). Within 3 weeks after administration, a maximum of 75% of the implanted material was degraded in rabbits, and a maximum of 95% of the implanted material was decomposed in rats within 2 weeks after administration. For biological degradation of poly (ethylene carbonate) a, a preliminary inflammatory reaction is necessary (including the invasion of neutrophilic white blood cells and other cells). It can be expected that the course of the inflammatory reaction will be species-specific, providing species-specific plasma drug drug profiles. This has been set for SMS-PA (FIG. 12). In rats, biodegradation of poly (ethylene carbonate) a occurs much faster than in rabbits. In rabbits, plasma SMS-PA levels increase slowly, reaching the constant release phase on the 9th day, and this phase lasts at least up to 21 days.

 EXAMPLE 27: Composition (w / o / w microparticles) having 0.0002% -2% rhIL-6 filling.

4 g of PEC is dissolved in 80 ml of methylene chloride by stirring using a magnetic stirrer. To this solution is added an appropriate amount of rhIL-6 (113.2 mg for 2%, 11.32 mg for 0.2%, etc.) dissolved in 6 ml of distilled water or water with a few drops of ethanol . The mixture is vigorously stirred using Ultra-Turax to disperse the IL-6 solution in the polymer phase (internal W / O phase). 1 g of gelatin A is dissolved in 200 ml of 1/15 M phosphate buffer (pH 7.4) at 50 ^{° C.} and the solution is cooled to 20 ^{° C.} (external W phase). W / O and W phases are intensively mixed. Through this, the internal W / O phase is crushed into small droplets that have been dispersed homogeneously in the external W phase. The resulting ternary emulsion is slowly stirred for 1 hour, the methylene chloride evaporates, and the droplets of the internal phase solidify into microparticles.

 After sedimentation (or centrifugation) of the microparticles, the supernatant is aspirated, and the microparticles are isolated by filtration under vacuum and washed with water to remove gelatin. Finally, the microparticles are dried in vacuum for 24 hours and sieved to obtain the final product.

 The encapsulation efficiency tested by HPLC and bioassessment ranges from 10 to 100%.

 EXAMPLE 28: Composition (s / o / w microparticles) having 0.0002% -2% rhIL-6 filling.

 The preparations are prepared as described in Example 27, with the exception that IL-6 is not dissolved in water. Instead of dissolving IL-6, the drug is dispersed directly in the polymer phase (O-phase). The encapsulation efficiency tested by HPLC and bioassessment ranges from 10 to 100%.

 Note: the amount of polymer, methylene chloride, water and drugs vary in a wide range, which does not affect the quality of the product. Get higher drug fillings - up to 20%. In the external phase, gelatin is replaced with other emulsifiers, such as polyvinyl alcohol, etc., and / or the concentration of emulsifier / buffer is changed. The described separation and drying processes are replaced by other well-known pharmaceutical technologies, such as filtration, lyophilization or spray drying.

 EXAMPLES 29-31: The use of IL-6 for the treatment of conditions caused by TNFα and / or IL-1.

 EXAMPLE 29: Animal model of multiple sclerosis: a model of chronic relapse of experimentally induced allergic encephalomyelitis in rat Lewis (XP-EAE).

 The experimentally induced rat allergic encephalomyelitis (EAE) is a well-studied experimental model of multiple sclerosis in humans (IMMUNOL. 5 (1966) 131-208, 113 (1974) 712.13 (1981) 3. J. PATH 47 (1965) 61 ) Rats are injected with other types of nerve tissue along with an adjuvant, and the resulting allergic reaction leads to damage to rat nerves, which mimic autoimmune lesions caused by multiple sclerosis. Rats become partially or completely paralyzed, and the severity of the disease is assessed with and without test drugs. A number of drugs, such as steroids and immunosuppressants, actively weaken the development of the disease, but are not able to prevent relapse after the disease is established.

 The model of chronic relapse of experimentally induced allergic encephalomyelitis (XP-EAE) J. NEUROIMMUNOL: 10 (1985) 159-166) is considered the most relevant model that closely mimics the current difficulties in treating patients with multiple sclerosis who have this disease. In this model, the disease is induced by administering a mixture of guinea pig spinal cord and Freund's complete adjuvant enriched in Mycobacterium tuberculosis. Typically, 75-80% of sensitized rats develop HR-EAE, giving 2-3 clinical relapses during the first 40 days. After 60-80 days, approximately 50% of rats with HR-EAE have the following relapses, followed by complete recovery in only 35% of all cases. In the remaining 65% of these animals, a progressive state of the disease is observed. Drug treatment begins on the 16th day after recovery from the first attack of the disease.

 Recombinant human interleukin-6 (rchIL-6, Sandoz), dissolved in brine, was administered intraperitoneally every 2 days starting at day 16 using 10 μg of IL-6 per rat (approximately 50 μg / kg). Control animals and animals in the IL-6 group suffered the usual severe attack of the disease (acute) on the 11-14th day. On a severity scale (from 0 - no disease to 4 - complete paralysis of the animal), the control group had an average score of 3.0, and IL-6 group - 3.2. The introduction of IL-6 every second day from the 16th to the 30th day (a total of 7 administrations) led to an almost complete suppression of the disease. Only one of the 5 IL-6 treated rats showed a mild recurrence of the disease (severity 0.4). In five of the 5 control animals, a second attack of the disease was observed with an average severity score of about 1.8 on the 16th day and a third attack of the disease on the 22-29th day. In IL-6 treated group, the following relapses were not observed.

 EXAMPLE 30: Animal model of arthritis: Borrelia-induced arthritis in mice with severe combined immunodeficiency (TCID).

 Lyme arthritis (or Lyme arthritis disease) is a unique form of chronic arthritis, as it can be called a stimulating event for him. The disease is one of the well-known characteristic features induced by infection with the spirochete Borrelia burgdorferi, which is transmitted by a tick. The features of synovial lesions in patients with Lyme arthritis are very similar to the symptoms of lesions in the synovial membrane in patients with rheumatoid arthritis. In both groups of patients, one can observe hypertrophy of the synovial lining cells, synovial cell hyperplasia, vascular proliferation and mononuclear cell infiltration in the regions of the subsynovial membrane. Many plasma cells, high endothelial venules, scattered macrophages and some dendritic cells have an intense presentation of the MHC class II antigen. In addition, cytokines such as IL-1, IL-6 and TNF-alpha were found in the synovial fluid of patients with various arthritis, thereby confirming the fact that these cytokines can contribute to the pathogenesis of joint destruction. A mouse model of Lyme arthritis has recently been created on TKID mice that are deficient in functional T and B cells (Immunology Today, 12: 11 (1991). Infection of immunodeficient Borrelia burgdorferi mice results in a raised and persistent oligoarthritis. Borrelia arthritis in TKID mice is sensitive to corticosteroids (prednisone 30 mg / kg subcutaneously) and is not sensitive to immunosuppressed agents like SIM (cyclosporin A) at doses not exceeding 30 mg / kg subcutaneously. It is considered as a good model of cytokine-induced arthritis, including yuchaya other types of arthritis for which the initiating event is not known with certainty.

Six week old C. B.-17 TKID mice (homozygous for TKID mutations obtained from Bomholtgard, Denmark, 5-6 animals / group) were inoculated with 100 mio. Borrelia burgdorferi organisms by subcutaneous injection at the base of the tail. As control animals, C.V.-17 immunocompetent mice (from the same source) were used. When injecting Borrelia burgdorferi, they do not develop a disease. Recombinant human IL-6 (rchIL-6, Sandoz, storage solution 5 mg / ml) was diluted with physiological saline and injected 5 times a week for 17 injections at a dose of 10 micrograms / mouse intraperitoneally. Mice were examined daily at random for the clinical symptoms of arthritis in the tibiotarsal and carpal-elbow joints. Clinical arthritis was recorded according to the following parameters:
- lack of symptoms
? doubtful symptoms
(+) redness of the joints
+ slight swelling
++ moderate swelling
+++ severe swelling of the tibiotarsal and carpal-elbow joints.

 At the time of the maximum development of clinical arthritis, the mice were sacrificed, and the joints were fixed in Schaffer'a solution, filled in plastic 9100, and stained with hematoxylineosine (see Table 5).

 TKID mice that have not been treated with IL-6 develop severe arthritis as a result of infection with Borrelia burgdorferi, starting from about 13 days after antigen injection. A low dose of rhIL-6 reduces the severity of arthritis within 60-75% of all affected animals.

 EXAMPLE 31: Murine model of septic shock.

 It was decided to study the effect of IL-6 in a mouse model of endotoxic shock using mice sensitive to d-galactosamine, since it is widely used as a model of human septic shock. Our methods and results are as follows.

Female OF1 mice weighing 18-22 g were injected with 0.2 ml intraperitoneally PBS solution containing 0.15 mg / kg lipopolysaccharide endotoxin (LPS) and 500 mg / kg d-galactosamine. The mice were divided into groups of 10 mice each and processed as follows:
Experiment 1 (see table 6),
Experiment 2 (see table 7).

 rchIL-6 (ILS 969, Sandoz), rchIL-2 (Sandoz) and rchIL-4 (Sandoz) were dissolved in PBS. All injections (0.2 ml volume) were administered intraperitoneally. In group 3 (experiment 1) and groups 3-8 (experiment 2), IL-6 and IL-2 were diluted in LPS / d-GAL solution and thus the mice received one injection of 0.2 ml. The numbers in parentheses indicate the dose of interleukin administered to each mouse. Multiple dosing of PBS was required to control intragroup variability due to the stress-induced response to control at different times before or after LPS administration.

 Mice survival was monitored for 48 hours. For statistical calculations, we used the Chi-quadratic test. As shown in FIG. 1, 24 hours after LPS administration, 9 out of 10 control mice died. Treatment with IL-6 3 hours before LPS administration or 2 hours after LPS administration reduced mortality by 60% (p = 0.12) and 70% (p = 0.26), respectively. On the other hand, the administration of IL-6 simultaneously with the administration of LPS decreased group mortality by 10% (p <0.01). The protective effects had a longer duration, so after 48 hours the mortality in group 3 slowly increased, for example, to 30%, reflecting a significant protective effect compared to the control group (p <0.01). Mortality of group 4 changed from 70% to 80%, while in groups 1 and 2 no changes were observed.

 Based on these results, we tested the effect of IL-6 in various doses. We gave IL-6 during LPS injections, because according to the first experiment, this was the optimal time. We also investigated the effect of IL-3 and IL-4, administered simultaneously with LPS, as a way to exclude possible artifacts due to the use of recombinant proteins in LPS / d-GAL preparations. We also tested whether IL-6 was effective in protecting mice from death from endotoxin at a dose of 100 μg / mouse, administered before or after LPS.

 The results of experiment 2 (Figure 2) correspond to the results of experiment 1. Also in this experiment, the treatment of IL-6 protected mice from death from endotoxin. When IL-6 was administered with LPS, the resulting defense 24 hours after LPS was dose-dependent at a dose of 20 (30% deaths, p = 0.03), 4 (50% deaths, p = 0.16) and 0.8 ( 70% of deaths, p = 0.61) μg / mouse, while at a dose of 100 μg / mouse (60% of deaths, p = 33), mice were less effectively protected than at 20 μg / mouse. Pretreatment or subsequent treatment with 100 μg IL-6 / mouse provided protection comparable to that observed when the same dose of IL-6 was administered with LPS. Similar mouse survival results were obtained 48 hours after LPS.

 IL-4, administered concurrently with LPS, was not effective in protecting mice from death from endotoxin, while IL-2 reduced the survival of mice.

Claims (24)

1. Poly (ethylene carbonate), biodegradable, containing units of ethylene carbonate of the formula A
- (C (O) -O-CH ₂ -CH ₂ -O -) - (A)
and having an ethylene carbonate content of from 70 to 100 mol%, an internal viscosity of 0.4 to 4.0 dl / g, measured in chloroform at a temperature of 20 ^{° C.} at a concentration of 1 g / dl, and a glass transition temperature of 15 to 50 ^{° C.} .  2. The polymer according to claim 1, characterized in that it has a molecular weight (MW) of from 100,000 to 2,000,000 as determined by gel permeation chromatography with methylene chloride as eluent and polystyrene as a reference.  3. The polymer according to claim 1, characterized in that it has an ethylene carbonate content of 90-100 mol%.  4. The polymer according to claim 1, characterized in that it has an internal viscosity, measured in chloroform at a concentration of 1 g / dl, equal to 0.4-3.0 dl / g 5. The polymer according to claim 1, characterized in that it has a glass transition temperature of from 18 to 50 ^o C.  6. The polymer according to claim 1, characterized in that it has units of ethylene carbonate and ethylene oxide. 7. The polymer according to claim 1, characterized in that after treatment with boiling water, distilled twice, for 5 hours has a glass transition temperature of from 18 to 50 ^o C. 8. The polymer according to claims 1-5 or 7, characterized in that it has as an accompanying link an ethylene oxide unit of the formula
- (CH ₂ -CH ₂ -O -) - (B)
9. The polymer according to claims 1 to 7, characterized in that it contains a terminal hydroxyl group. 10. The method of producing the polymer according to claims 1 to 7, which consists in the fact that ethylene oxide and carbon dioxide are polymerized at a temperature of from 10 to 80 ^o C in a molar ratio of 1: 4 to 1: 5 in the presence of a catalyst, which is obtained as a result the reaction of diethylzinc and a solvent selected from the group consisting of water, acetone, diol, di - or triphenol.  11. The method according to claim 10, characterized in that a catalyst obtained from diethylzinc and di- or triphenol in a molar ratio of from 2: 1 to 1: 2 is used.  12. The method according to claim 10, characterized in that the use of a catalyst obtained from diethylzinc and diol in a molar ratio of from 0.9: 1 to 1: 0.9.  13. The method according to p. 12, characterized in that the use of a catalyst obtained from diethylzinc and ethylene glycol.  14. The method according to claim 10, characterized in that the catalyst obtained from diethylzinc and 1,3,5-trihydroxybenzene is used.  15. The method according to claim 10, characterized in that it is implemented in a dissolving and dispersing reaction system of an organic solvent and carbon dioxide. 16. The method according to claim 10, characterized in that it is implemented at a pressure of from 20 to 70 bar and a temperature of from 10 to 80 ^o C.  17. The method according to claim 10, characterized in that receive the polymer of ethylene carbonate with a terminal hydroxyl group according to claim 9.  18. A pharmaceutical composition comprising poly (ethylene carbonate) according to claims 1-7 and a pharmacologically active compound.  19. A pharmaceutical composition comprising a pharmaceutically active compound and the poly (ethylene carbonate) according to claim 1, capable of non-hydrolytic surface erosion.  20. The pharmaceutical composition according to claim 19, characterized in that it has a linear correlation of the release of the active compound and non-hydrolytic degradation of the mass of poly (ethylene carbonate), as well as the protection of the active compound in poly (ethylene carbonate).  21. The pharmaceutical composition according to claims 18 to 20, characterized in that it contains an active protein or peptide as a pharmacologically active compound.  22. The pharmaceutical composition according to claims 18-21, characterized in that it contains granulocyte-macrophage-colony-stimulating factor and granulocyte-colony-stimulating factor as an active compound.  23. The pharmaceutical composition according to claims 18-22, characterized in that it further comprises additives in or on poly (ethylene carbonate).  24. The pharmaceutical composition according to claims 18-23, characterized in that it is in the form of microparticles or an implant.  25. The pharmaceutical composition according to paragraph 24, characterized in that it is intended for the treatment of autoimmune or inflammatory conditions.

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