SK44795A3 - Composition based on polyoxyethylene-polyoxypropylene block copolymers and container containing it - Google Patents

Abstract

A sealed pharmaceutically acceptable container which contains in a vacuum or in an inert atmosphere a sterile aqueous injectable solution of a block copolymer of polyoxypropylene/polyoxyethylene, the solution being substantially free from an antioxidant and being buffered at a pH from 5.5 to 6.5.

Description

A composition based on polyoxyethylene-polyoxypropylene block copolymers and a container thereof

Technical field

The present invention relates to a stable pharmaceutical composition of a polyoxyethylene-polyoxypropylene block copolymer.

BACKGROUND OF THE INVENTION

Certain surfactant polyoxyethylene-polyoxypropylene block copolymers have recently been found to have beneficial effects in veterinary and human medicine. In particular, the copolymers may be used to treat circulatory disorders, alone or in combination with other agents, such as fibrinolytic enzymes, anticoagulants, free radical scavengers, anti-inflammatory agents, antibiotics, membrane stabilizers and / or the wash environment. These uses are described in U.S. Pat. 3,641,240, 4,801,452, 4,873,083, 4,879,109,

937 070,

032 394,

071 649,

198 211,

837 014,

028 599, 5,047 236, 5,089,260,

897 263,

030 448, 5 064 643, 5 152 979

997 644,

039 520, 5,078,995,

017 370, 5,041,288, 5,080,894, all of which are incorporated herein by reference.

Surface-active copolymers act effectively on disorders of the circulatory system where pathologically hydrophilic interaction between cells and / or molecules occurs. This interaction is believed to be caused

(1) higher than normal fibrinogen concentration;

(2) formation of intravascular or locally soluble fibrin, in particular high molecular weight fibrinogen,

Increasing the friction in the microvasculature; or

4) mechanical or chemical trauma to blood components.

These disorders cause an increase in the pathologically hydrophobic interactions of blood components such as cells or molecules. It is believed that fibrin, particularly soluble fibrin, increases cell adhesion to one another, increases markedly friction in small blood vessels, and increases blood viscosity, especially at low shear rates. It is also believed that the effects of the surfactant copolymers exhibit a substantially lubricating effect as they reduce the friction caused by adhesion.

Commercially available surface-active polyoxyethylene-polyoxypropylene block copolymers generally contain antioxidants. In particular, formulations of poloxamer 188, available from BASF, Parsippany (New Jersey, USA), include butylated hydroxytoluene (BHT). This antioxidant is not standardized for pharmaceutical use. In addition, antioxidants tend to be hydrophobic and insoluble in aqueous media, and some may also present toxicity problems. These substances are clearly undesirable in a solution for injection for medical use. The present invention therefore provides an aqueous block copolymer solution substantially free of such antioxidant agents.

The absence of an antioxidant in block copolymer solutions tends to cause their oxidation and degradation. This results in a shorter chain of the molecule and by-products, such as organic acids (e.g. acetic acid), resulting in a lower pH of the solution to 4 or even lower. Furthermore, it has been observed that at lower pH values, the degradation of the copolymer is faster and more extensive. The present invention therefore relates to a stable aqueous solution of a block copolymer.

EP-A-103 290 describes aqueous pharmaceutical compositions of polyoxypropylene and polyoxyethylene which are adjusted to a physiologically acceptable pH, preferably from 6 to 8, by addition of electrolytes and buffers. However, a pharmaceutical composition of a polyoxyethylene-polyoxypropylene block copolymer is not described, and neither of the above-mentioned disadvantages associated with such a polymer is described or indirectly indicated. Similarly, U.S. Pat. No. 4,938,961 discloses an aqueous solution of polypropylene glycol but does not mention solutions of a polyoxyethylene-polyoxypropylene block copolymer.

SUMMARY OF THE INVENTION

In addition to the above, another feature of the present invention is an aqueous solution of a polyoxyethylene-polyoxypropylene block copolymer suitable for injection, in particular for intravenous injection.

Accordingly, the present invention provides a pharmaceutically acceptable container which, under reduced pressure or in an inert atmosphere, comprises a sterile aqueous injection solution of a block polymer of Formula I

HO (C ₂ H ₄ O) _b (C ₃ H ₆ O) _a (C ₂ H ₄ O) _b H (I), in which a

is an integer such that the hydrophobic component represented by (C ^ H? O) has a molecular weight of 950-4000 daltons, preferably about 1200 to 3500 Daltons and b is an integer such that the hydrophilic moiety represented by (C ₂ H ₄ O) from 50 to 90% by weight. copolymer, wherein the solution is substantially devoid of antioxidant and is buffered to a pH of from 5.5 to 6.5.

A preferred block copolymer of formula I is a copolymer in which the molecular weight of the hydrophobe (C ₃ H? O) is approximately 1750 daltons and the total molecular weight of the copolymer is approximately 8400 Daltons. A particular example of such a block copolymer is the copolymer, which is referred to as poloxamer 188 (BASF, Parsippany, New Jersey, USA). An analysis of the structure of poloxamers and poloxamine block copolymers can be found in IR Schmolka, A Review of Block Polymer Surfactans, J. Am. Oil Chemists Soc. 54, 110-116 (1977), which is incorporated herein by reference.

Commercially available sources of poloxamer 188 are reported to have a molecular weight of about 8400 daltons. In fact, the block copolymer consists of molecules having a molecular weight from less than 3000 daltons to above 20,000 daltons. Molecularity and molecular distribution in the commercially available poloxamer 188 can be illustrated by a broad primary and secondary peak, which can be detected by gel chromatography as described in WO 92/16484.

High molecular weight components, i. components having a molecular weight greater than 15 kDa are present in the commercially available poloxamer 188 usually in an amount of up to 3% by weight. block copolymer or more. Such significant amounts may cause an increase in unwanted side effects in clinical block copolymer applications. In particular, these components have a longer elimination phase half-life than the bulk of the block copolymer and thus accumulate in plasma and kidney. In addition, these high molecular weight components may be responsible for activating the complementary system. Thus, it is preferred that the block copolymer for use in the present invention is free of, at least to a significant extent, i.e. to less than 1% by weight, preferably to 0.5 or 0.2% by weight. any molecules having a molecular weight greater than 15 kDa.

The standard measure of the molecular weight distribution of a polymer is its polydispersity. This relates to and is described in WO 92/16484, the contents of which are incorporated herein by reference. Briefly, polydispersity 1.0 is an indicator of a polymer in which all molecules have the same molecular weight. The conventional polymer may have a polydispersity of from 2 to 5. The polyoxyethylene-polyoxypropylene block copolymer used in the present invention has a polydispersity of less than 1.4, preferably 1.3 or 1.2, or also 1.1.

The surfactant block copolymer can be produced by condensation of ethylene oxide and propylene oxide at elevated temperature and pressure in the presence of a basic catalyst. However, there are statistical changes in the number of monomer units that combine to form the polymer chain of each copolymer. The given molecular weight is approximately the average weight of the copolymer molecules in each formulation. A more detailed analysis of the production of these copolymers is found in U.S. Pat. No. 2,674,619, which is incorporated herein by reference. Preferred forms of the block copolymer, i. forms which are devoid of any substantial number of molecules having a molecular weight greater than 15 kDa or having a polydispersity of less than 1.4 can be obtained as described in WO 92/16484.

Certain commercially available block copolymers, such as poloxamer 188, may exist in a form that contains an antioxidant. Before use according to the invention, the antioxidant is to be removed from the copolymer, e.g. by filtration or using another means known in the art. Preferably, however, the block copolymer is obtained in a form which is substantially free of the antioxidant.

The amount of block copolymer contained in the aqueous solution for injection is preferably from 135 to 165 mg / ml, in particular about 150 mg / ml.

The pH of the aqueous solution for injection is preferably about 6.

The aqueous solution for injection is buffered to the desired pH using a buffering agent. Examples of such buffering agents include citrate (e.g., sodium citrate and citric acid). The concentration of the buffering agent, especially the citrate buffering agent, should preferably be 0.005 to 0.05 molar, especially about 0.01 molar.

Although a pharmaceutically acceptable co-solvent may optionally be present in addition to water, it is preferred that the medium for the aqueous injection solution be wholly or substantially aqueous.

The aqueous solution for injection preferably has such tonicity with the patient's blood serum that it avoids undesirable side effects. If it is desired to increase the tonicity of the aqueous solution for injection, the substantially isotonic solution may be obtained by adding a pharmaceutically acceptable composition capable of increasing the tonicity of the solution to the desired level. Examples of such a composition are well known in the art and include dextrose, sodium chloride and mixtures thereof.

The aqueous solution for injection may be obtained in sterile form by filtration or by autoclaving.

The preparation of the aqueous solution for injection and its filling into pharmaceutically acceptable containers is preferably carried out according to methods known in the art and under conditions designed to minimize the oxygen content of the solution produced or above.

Examples of a pharmaceutically acceptable container include containers that are made of plastic or glass, such as vials, ampoules and vials. The container may optionally be colored, such as e.g. to an amber color to reduce exposure of the aqueous injection solution to ultraviolet radiation and possible degradation. According to another embodiment, the cartridges may be colored, but packaged in an opaque cardboard box.

Preferably, the aqueous solution for injection is contained in an inert atmosphere, which is nitrogen.

usefulness

The surfactant copolymer may be used to treat circulatory disorders caused or caused by the pathological hydrophobic interaction of blood components. Examples of such disorders include myocardial infarction, stroke, infarction of the intestines or other tissues, malignancy, adult respiratory distress syndrome (ARDS), multiple intravascular coagulation (DIC), diabetes, constant angina pectoris, hemolytic uremic syndrome, hemolytic uremic syndrome, , retained fetus, eclampsia, malignant hypertension, sickle cell disease, burn, fracture, shock-induced trauma, surgery, sepsis, bacterial, parasitic, viral and ricketsial infections that help activate the coagulation system, central nervous system trauma and central nervous system trauma or immediately after the procedure.

The surfactant copolymer is also effective in enhancing collateral circulation to intact tissues with compromised blood supply. Such tissues often adjoin areas where vascular occlusion has occurred. There is a mechanism to reduce pathological hydrophobic interactions in small blood vessels. Circulatory disorders in which surface active copolymers are effective include cerebral thrombosis, cerebral embolism, myocardial infarction, unstabilized angina pectoris, transient cerebral ischemic seizures, intermittent foot curvature, plastic and reconstructive orthopedic surgery, angioplasty, angioplasty if a turnstile is used. The copolymer can also be used to protect organs for transplantation.

The aqueous injection solution containing the block copolymer may be administered to the patient by injection or preferably by infusion. The usual venue for administration will be a peripheral vein. The injection solution is normally administered over 2 minutes. The infusion is normally carried out with a solution that is contained in an infusion bag or container or by means of an electric infusion pump. The solution may be released from the infusion bag or container into the patient under the influence of gravity or using an infusion pump.

An effective amount of a block copolymer for treating a patient suffering from a circulatory disorder will, of course, depend upon a number of circumstances, including e.g. the age and weight of the patient, the precise condition requiring treatment, the route of administration, and will ultimately be at the discretion of the attending physician. However, an effective amount will clearly be generally from 0.2 to 3.0 g / kg, preferably from 1.5 to 2.5 g / kg of body weight, when administered to a patient for a period of from 1 to 48 hours.

DETAILED DESCRIPTION OF THE INVENTION

The following examples serve to illustrate the invention.

Example 1

For a batch of 5000 liters, the following production and manufacturing process is carried out using nitrogen protection.

For batch poloxamer 188, NF ¹ sodium chloride, USP sodium citrate (dihydrate), USP citric acid (anhydrous), USP water for injections, USP

750,00 kg

15,40 kg 11,90 kg

1.83 kg as needed

5000.0 liters

It contains less than 0,2% of molecules having a molecular weight greater than 15 kDa and is provided in this form

1. Prepare approximately 4000 liters of water for injections preheated to 70 to 80 ° C in a suitable container (container 1). A further 1000 liters of water for injections preheated to 70-80 ° C are prepared in a second vessel (vessel # 2).

2. The water in both vessels is purged with filtered nitrogen gas. The contents of the vessels were cooled to room temperature while being continuously purged with filtered nitrogen gas.

3. Dissolve citric acid, sodium citrate and sodium chloride under a nitrogen atmosphere and bring the resulting solution into water in vessel no. 1. Continue to purge with filtered nitrogen gas.

4. The upper part of the space is covered with filtered nitrogen gas and then purged with nitrogen. The block copolymer is slowly added to the solution and mixed until dissolved.

Note: While stirring, cover the top of the space with filtered nitrogen gas.

5. Add sufficient water for injection, pre-purged with nitrogen (from vessel # 2) to bring the batch to final volume and mix.

6. Filter the solution through a 0.45 gm membrane filter or equivalent into a suitable clean nitrogen purged container.

7. While maintaining the cleanliness, place approximately 500 ml of the solution in pre-washed, Type 1 flint glass containers of 650 ml.

8. Subject to cleanliness, a suitable bottle cap is applied without inserting it.

9. Apply reduced pressure to the top of the filled bottle and insert the cap into the throat.

10. An airtight seal is performed.

11. Heat sterilize the product.

12. Cool the product to room temperature and then stir until uniform.

13. The bottle is stored in individual cardboard boxes to protect the product from light.

1 ml of the stock solution contains the following amounts of the ingredients of the composition described above:

Per millimeter

poloxamer 188, NF ¹ 150.0 mg sodium chloride, USP 3.08 mg sodium citrate (dihydrate), USP 2.38 mg citric acid (anhydrous), USP 0,366 mg

water for injections, USP together 1.0 ml as needed ¹ Contains less than 0.2% of molecules having a molecular weight greater than 15 kDa and is provided in this form

The aqueous solution for injection obtained in this manner is a clear, colorless solution which does not contain particulate, turbid or swollen matter and is stable, as can be seen from the following:

- 11 Degradation products

Stock-Poloxamer 188 (ppm)

tion PH D mw Mn 1.S%. oh act for meth form storage 5.8 1.21 5,718.0 4,713.0 99.3 25 <1 21 <1 2 • UV: 7 days 5.8 - it's not - 98.4 25 3 24 <1 2 • 14 days 5.8 - stated it's not stated - 99.1 20 3 20 <1 2 fluorine: 7 days 5.8 ' " it's not stated 100.3 24 7 25 <1 1 14 days 5.8 it's not stated 99.0 19 7 19 <1 1 Deň: 32 ° C 1 month 5.8 1.24 5,438.0 4,408.0 101.6 22 <1 19 <1 4 4 months 5.8 1.24 5,418.0 4,369.0 98.3 33 1 29 <1 6 Deň: 32 ° C • 4 months 5.7 1.26 5,437.0 4,326.0 98.6 36 <1 33 <1 5 • Deň: 29 ° C 4 months 5.6 1.25 5,429.0 4,354.0 99.2 35 <1 33 <1 5

Explanation: ppm: parts per million oh: acetaldehyde D: polydispersity (Mw / Mn) act: acetone ON THE: unavailable for: propionaldehyde fluorine: Fluorescent met: methanol l.sec .: marked force form: formaldehyde

Example 2

The procedure of Example 1 was repeated for a batch size of 200 liters using the following production. Prepare 160 liters of water for vessel no. 1 and 40 liters of water in container no. Second

poloxamer 188, NF ¹ 30,00 kg • sodium chloride, USP 0,616 kg sodium citrate (dihydrate), USP 0.476 kg • citric acid (anhydrous), USP 0,0732 kg Water for Injection, USP as needed

Total 200.0 liters ¹ Contains less than 0.2% of molecules having a molecular weight greater than 15 kDa and is provided in this form

The resulting aqueous injectable solution has a physical appearance similar to that of Example 1. The stability values shown below are achieved.

Degradation products

Stock-Poloxamer 188 (ppm) pH D Mw Mn% l.s. oh act for met form

storage 5.8 1.24 5,550.0 4,482.0 99.8 32 <1 11.0 <1 <1 UV: 7 days 5.7 1.28 5,764.5 4,509.5 99.7 23 4 24 1 3 14 days 5.9 1.29 5,789.0 4,498.0 98.8 22 7 23 1 1 fluorine: 7 days 5.8 1.29 5,852.0 4,535.5 99.2 24 9 23 2 3 14 days 5.9 1.29 5,873.0 4,545.5 98.1 25 12 25 2 4

(continued table)

Stock-Poloxamer 188 (ppm)

tion PH D mw Mn L.sec%. oh act for meth form Deň: 32 ° C 1 month 5.8 1.26 5,591.5 4,428.0 104.8 33 1 29 <1 7 2 months 5.7 1.35 5,411.0 3,996.0 101.7 35 1 28 2 10 Deň: 32 ° C 3 months 5.8 1.25 5,414.0 4,327.0 99.6 30 <1 22 <1 8 Deň: 29 ° C 3 months 5.9 1.26 5,328.0 4,228.0 98.6 22 <1 19 <1  4

Explanation:

ppm: parts per million

D: polydispersity (Mw / Mn)

N / A: Not available

Fluorine: Fluorescent

l.s .: indicated force ach: acetaldehyde act: acetone for: propionaldehyde met: methanol form: formaldehyde

Claims (18)

PATENT CLAIMS 1. A sealed pharmaceutically acceptable container which, under reduced pressure or under an inert atmosphere, contains a sterile aqueous injection solution of a block polymer of the formula I HO (C ₂ H ₄ O) _b (C ₃ H ₆ O) _and (C ₂ H ₄ O) _b H (I), in which a is an integer such that the hydrophobic component represented by (C ₃ H _g O) it has a molecular weight of 950 to 4000 daltons and b is an integer such that the hydrophilic moiety represented by (C ₂ H ₄ O) constitutes from 50 to 90% by weight. copolymer, wherein the solution is substantially devoid of antioxidant and is buffered to a pH of from 5.5 to 6.5. Container according to claim 1, characterized in that the molecular weight of the homophobic component is from 1200 to 3500 daltons. The container of claim 2, wherein the molecular weight of the hydrophobic component is about 1750 daltons and the total molecular weight of the copolymer is about 8400 daltons. The container of any one of the preceding claims, wherein the block copolymer is substantially free of any molecules having a molecular weight greater than 15,000 daltons. The container of claim 4, wherein the amount of molecules having a molecular weight of greater than 15,000 daltons is less than 1%. The container of claim 5, wherein the amount is less than 0.5%. A container according to any one of the preceding claims, characterized in that the block copolymer has a polydispersity of less than 1.4. Cartridge according to claim 7, characterized in that the polydispersity is less than 1.3. A container according to claim 8, characterized in that the polydispersity is less than 1.2. A container according to claim 9, characterized in that the polydispersity is less than 1.1. The container of any one of the preceding claims, wherein the block copolymer is present in an amount of from 135 to 165 mg / ml. The container of claim 11, wherein the amount corresponds to about 150 mg / ml of the solution. A container according to any one of the preceding claims, characterized in that the pH is about 6. A container according to any one of the preceding claims, wherein the solution is buffered using citrate as a buffering agent. The container of claim 14, wherein the concentration of the citrate buffering agent is 0.005 to 0.05 molar. The container of claim 15, wherein the concentration is about 0.01 molar. A container according to any one of the preceding claims, wherein the solution is substantially isotonic with human blood serum. Container according to any one of the preceding claims, characterized in that the inert atmosphere is nitrogen.