HUT75701A - Composition based on polyoxyethylene-polyoxypropylene block copolymers and container containing it - Google Patents

Description

The present invention relates to a stable pharmaceutical composition comprising a polyoxypropylene / polyoxyethylene block copolymer.

Certain surfactant polyoxypropylene / polyoxyethylene block copolymers have been found to be beneficial in veterinary and human medicine. These copolymers may be used alone or with other agents for the treatment of circulatory disorders, such as fibrinolytic enzymes, anticoagulants, free radical scavengers, anti-inflammatory agents, antibiotics, membrane stabilizers and / or. These applications, together with the perfusion medium, are covered by 3,641,240,

4 801 452, 4 873 083, 4,879 109; 4,837 014 4 897 263 4 937 070 4 997 664, 5,017 370 5,028 599 5 030 448, 5 032 394 5 039 520 5,041 288 5,047 236 5 064 643, 5 071 649, 5 071 649, 5,078 995 ,. 5,080 894, 5 089 260 5 152 979, 5: 182 106 and 5,198 , 211 No. America United

It is described in U.S. Patents, which are incorporated herein by reference.

Surfactant copolymers are effective for circulatory disorders in which abnormal hydrophobic interaction takes place between cells and / or molecules. It is believed that these interactions are (1) higher than normal levels of fibrinogen; (2) formation of intravascular or local soluble fibrin, in particular high molecular weight fibrin; (3) increased friction in the capillary system; or (4) caused by mechanical or chemical injury (trauma) to the blood components or to injury to the blood components. These disorders cause an increase in pathological hydrophobic interactions between blood components (cells and molecules). It is believed that fibrin, especially soluble fibrin, enhances cell adhesion, significantly increases friction of small blood vessels, and increases blood viscosity (especially at low shear forces). It is believed that the effects of surfactant copolymers are essentially lubricating as they reduce the friction caused by adhesion.

Commercially available surfactant polyoxypropylene / polyoxyethylene block copolymers generally contain antioxidants. Poloxamer 188, available from BASF (Parsippany, New Jersey, USA), contains BHT (butylated hydroxytoluene). This antioxidant is not certified for pharmaceutical use. In addition, antioxidants are hydrophobic and insoluble in aqueous media, and some cause toxicity problems. This is obviously undesirable for an injectable solution for medical use. Accordingly, it is an object of the present invention to provide an aqueous solution of block copolymers which is substantially free of such antioxidants.

The lack of antioxidants in block copolymer solutions results in the oxidation and degradation of the copolymers, leading to the formation of shorter-chain molecules and by-products such as organic acids (e.g. acetic acid), to pH 4 or lower.

- 4 decrease. It has also been found that the lower the pH, the faster and more thorough the degradation of the copolymer. Accordingly, an object of the present invention is to provide an aqueous solution of block copolymers.

EP-A-103290 describes aqueous pharmaceutical formulations of polyoxypropylene and polyoxyethylene adjusted to a physiologically acceptable pH (preferably 6-8) by the addition of electrolytes and buffers. However, the said patent does not disclose a pharmaceutical composition made of a polyoxypropylene / polyoxyethylene block copolymer, nor does it disclose the aforementioned disadvantages associated with such a polymer. Similarly, U.S. Pat. No. 4,938,961 discloses an aqueous solution of polypropylene glycol, but does not mention polyoxypropylene / polyoxyethylene block copolymer solutions.

The present invention further relates to an aqueous solution of a polyoxypropylene / polyoxyethylene block copolymer for injection, in particular for intravenous injection.

Thus, a pharmaceutically acceptable sealed container is provided which, under vacuum or in an inert atmosphere, is a block copolymer of formula I

HO (C ₂ H4O) contains _a (C2H4O) injectable, sterile aqueous solution of b (C3HeO) TOH (I) substantially free of antioxidants, and 5.5 to 6.5 pH solution which * • 4 · ··· «

Buffered. In formula I, a is an integer such that the hydrophobic moiety of (CsHeO) is 950-4000 Daltons, preferably about 1200-3500 Daltons, and b is an integer such that the (C2H4O) hydrophilic moiety is 50-95 m / m%.

In the preferred block copolymer of formula I, the hydrophobic moiety of (CsH5O) is about 1750 Daltons and the total molecular weight of the copolymer is about 8400 Daltons. A specific example of such a block copolymer is a copolymer called poloxamer (BASF, Parsippany, New Jersey, USA). Poloxamers and poloxamine block copolymers are described in Schmolka, I.R .: Review of Block Polymer Surfactants, J. AM. 54, 110-116 (1977), incorporated herein by reference.

Poloxamer 188 has commercially available sources with an estimated molecular weight of approximately 8400 Daltons. In reality, block copolymers consist of molecules with molecular weights ranging from less than 3,000 Daltons to more than 20,000 Daltons. The molecular diversity and distribution of commercial poloxamer 188 are characterized by broad primary and secondary peaks detected by permeation gel chromatography (WO 92/16484).

The high molecular weight components, i.e., the molecular weight greater than 15 kD, are normally present in the commercially available poloxamer 188 in a ratio of 3% w / w to 9% or more per block copolymer. This significant amount may cause undesirable side effects in the clinical use of the block copolymer. The elimination half-lives of these components are greater than those of the majority of the copolymer and thus accumulate in the plasma and kidneys. In addition, high molecular weight components may be responsible for activating the complement system. Accordingly, it is preferred that the block copolymer of the present invention is at least substantially free of molecules having a molecular weight greater than 15 kD, i.e. less than 1% w / w, preferably less than 0.5% or 0.2% w / w. .

The standard measure of molecular weight distribution of the polymer is the polydispersity described in WO92 / 16484 (incorporated herein by reference). A polydispersity of 1.0 is a polymer in which all molecules have the same molecular weight. Polydispersity of a typical polymer from 2

Up to 5. The polyoxypropylene / polyoxyethylene block copolymer of the present invention preferably has a polydispersity of less than 1.4, preferably less than 1.3 or 1.2 or more preferably less than 1.1.

The surfactant block copolymer can be prepared by condensing ethylene oxide and propylene oxide at high temperature and pressure in the presence of a basic catalyst. In each copolymer, a monomer fused to form a polymer chain

- However, there are statistical variations in the number of units. The molecular weight values given are approximate values of the average weight of the copolymer molecules of each formulation. A more detailed description of the preparation of these copolymers is given in U.S. Patent No. 2,674,619. Preferred forms of block copolymers, that is, substantially free of 15 kD molecules or having a polydispersity of less than 1.4, may be prepared by the process described in WO92 / 16484.

Certain commercially available block copolymers, such as poloxamer 188, may exist in antioxidant form. Prior to use according to the invention, the antioxidant must be removed from the copolymer, for example by filtration or other known methods. However, the block copolymer is preferably obtained in a form which is already free of antioxidants.

The amount of block copolymer in the injectable aqueous solution is preferably 135-165 mg / ml, preferably 150 mg / ml. The pH of the injectable aqueous solution is preferably ca. 6th

The desired pH of the injectable aqueous solution is adjusted with a buffer. An example of such a buffer is the citrate buffer (e.g., sodium citrate / citric acid). The concentration of the buffer, in particular the citrate buffer, should preferably be 0.005-0.05 M,

preferably 0.01 M.

Although a pharmaceutically acceptable common solvent may be present in addition to water, it is preferable that the medium for the injectable aqueous solution be wholly or substantially water.

The injectable aqueous solution with the patient's blood serum preferably exhibits a tonic effect which eliminates unwanted side effects. When it is necessary to increase the tonicity of the injectable aqueous solution, a substantially isotonic solution may be obtained by adding a pharmaceutically acceptable agent capable of raising the tonicity of the solution to the desired level. Examples of such agents are well known and include dextrose and sodium chloride, and

mixtures.

The injectable aqueous treatment can be sterilized by filtration or autoclaved

The preparation of the injectable aqueous solution and its filling into pharmaceutically acceptable containers are preferably carried out according to known methods, under conditions which minimize the presence of oxygen in or above the solution.

Examples of pharmaceutically acceptable containers include plastic and glass containers such as vials,

ampoules and bottles. The tanks may be optionally colored, for example, to amber to reduce UV light acting on the injectable aqueous solution and to reduce potential degradation. Alternatively, leaving the containers colorless, I can wrap them in opaque cardboard.

The injectable aqueous solution is preferably kept under inert atmosphere, in this case nitrogen gas.

Surfactant copolymers are useful in the treatment of circulatory disorders caused or caused by abnormal hydrophobic interactions of blood components. Such disorders include myocardial infarction, cerebral haemorrhage, intestinal or other tissue infarction, malignancies, adult respiratory pain syndrome (ARDS), disseminated intravascular coagulation (DIC), diabetes, unstable angina pectoris, coronary heart disease, disintegration syndrome, heat stroke, fetal retention, convulsions, malignant hypertension, sickle cell anemia, burns, bruising injuries, fractures, traumatic shock, major surgery, blood poisoning, bacterial anemia that promotes coagulation system, (during or immediately after any major surgery).

The surfactant copolymer is also effective in enhancing collateral circulation to endangered non-injured tissue. Such tissues are often adjacent to vascular occlusion sites. This mechanism appears to reduce abnormal hydrophobic interactions in the capillaries. Circulatory disorders (for which surfactant copolymers are effective) include cerebral thrombosis, cerebral embolism, myocardial infarction, labile angina pectoris, transient loss of blood supply (ischemia), intermittent claudication, plastic and restorative surgery, vascular surgery, peripheral vascular surgery and orthopedic surgery (especially when using tourniquet; Esmarch's bandage). Copolymers may also be used for preservation of organs for transplantation.

An injectable aqueous solution of the block copolymer may be administered by bolus injection or, preferably, by infusion. The peripheral vein.

a suitable site for administration under normal circumstances

The bolus injection is usually given over a period of two minutes. Infusion treatment is generally performed using a solution in an infusion bag, bottle, or electronically operated infusion pump. The solution may be delivered from the infusion bag or bottle by gravity or an infusion pump.

The effective amount of block copolymer for treating a patient with circulatory disorder will, of course, depend on a number of factors, including the age and

body weight, the exact condition that requires treatment, the route of administration, and ultimately the judgment of the attending physician. However, the effective dose will generally be from 0.2 g / kg body weight to 3.0 g / kg body weight, preferably from 1.5 g / kg body weight to 2.5 g / kg body weight, administered over a period of 1 to 48 hours. person.

The following examples are provided to illustrate the invention.

Example 1

5,000 liters batch was applied with nitrogen protection)

Poloxamer 188, NF ¹

Sodium chloride, USP

Sodium citrate (dihydrate), USP Citric acid anhydrous, USP Water for injections, USO

TOTAL of the following formulation and preparation (throughout the process kg / dose

750.00

15.40

11.90

1.83 sufficient for a volume of 5000.0 liters (less than 0.2% of molecules of ¹ 15 kDa molecular weight)

1) Approximately 4000 liters preheated (70-80 ° C)

water for injection is collected in a suitable vessel (vessel 1), while the remaining 1000 liters of preheated (70-80 ° C) water is collected in another vessel (vessel 2).

2) Δ water was purged with filtered nitrogen gas in each vessel and cooled to room temperature with continuous nitrogen purge.

3) Dissolve the citric acid, sodium citrate and sodium chloride in water flushed with nitrogen in vessel 1 and continue flushing with filtered nitrogen.

4) Fill the space above the solution with filtered nitrogen gas and complete the purge with nitrogen gas. The block copolymer is slowly added to the solution and stirred until dissolved (the volume of filtered solution over the solution is continued while stirring).

5) To make up the dose to the final volume, add a sufficient amount of water (from tank 2), previously flushed with nitrogen gas, to the solution.

6) Filter the solution through a 0.45 micrometer membrane filter into a suitable clean nitrogen purged container.

7) Approximately 500 mL of the solution is filled under clean conditions into a pre-washed 650 mL Type 1 quartz glass bottle.

8) The bottles shall be fitted with a suitable closure under clean conditions without being pushed into the bottle.

9) Vacuum the space above the solution and push the stopper into the filled bottles.

10) Seal the tops of the bottles.

11) The product is sterilized.

12) The product was cooled to room temperature and stirred until uniform.

13) Store the bottles in cardboard boxes to protect the product from light.

The amount of the above components in a 1 ml dose is as follows:

mg / ml

Poloxamer 188, NF ¹ 150.0

Sodium chloride, USP 3.08

Sodium citrate (dihydrate), USP 2.38

Citric acid anhydrous, USP 0.366

Water for injection, USO sufficient

For a total volume of 1.0 ml

The injectable aqueous solution thus prepared is a clear, colorless, stable solution, free from particulate matter, opacity or cloudiness, as demonstrated by the following data:

Po'loxamer 188 Decomposition Products (ppm)

Storage pH D Mr * M _n jt% ach act pro met form

Away

5.8 1.21 5718.0 4713.0 99.3 25 <1 21 <1 2 UV; 7 Sun 5.8 - NR - 98.4 25 3 24 <1 2 14 days 5.8 - NR - 99.1 20 3 20 <1 2 F. 7 Sun 5.8 - NR 100.3 24 7 25 <1 1 14 Sun 5.8 - NR - 99.0 19 7 19 <1 1 50 ° C 1 hr. 5.8 1.24 5438.0 4408.0 101.6 22 <1 19 <1 4 4h. 5.8 1.24 5418.0 4369.0 98.3 33 1 29 <1 6 40 ° C 4h. 5.7 1.26 5437.0 4326.0 98.6 36 <1 33 <1 5 30 ° C 4h. 5.6 1.25 5429.0 4354.0 99.2 35 1 33 <1 5

ppm: parts per million ach: acetaldehyde D: polydispersity (Mr / Mn) act: acetone NR: not available pro: propionaldehyde F.: fluorescence meth: methanol j. t. : indicated durability formation : formaldehyde

h: month

- 15 Example 2

The procedure described in Example 1 was repeated to prepare a 200 L portion using the following formulations, collecting 160 L in Flask 1 and 40 L in Flask 2.

Poloxamer 188, NF ¹

Sodium chloride, USP

Sodium citrate (dihydrate), USP Citric acid anhydrous, USP Water for injections, USO

ALTOGETHER

30.00 kg

0.616 kg 0.476 kg 0.0732 kg is sufficient for a volume of 200.0 liters

The resultant injectable aqueous solution was similar in physical characteristics to that of Example 1. The following stability data were obtained.

- 16 ν '

Poloxamer 188 Degradation Products (ppm)

Storage pH D Mn% w / w ach act pro met form

Away

5.8 1.24 5550.0 4482.0 99.8 32 <1 11.0 <1 <1 UV; 7 days 5.7 1.28 5764.5 4509.5 99.7 23 4 24 1 3 14 days 5.9 1.29 5789.0 4498.0 98.8 22 7 23 1 1 F. 7 days 5.8 1.29 5852.0 4535.5 99.2 24 9 23 2 3 14 days 5.9 1.29 5873.0 4545.5 98.1 25 12 25 2 4 50 ° C for 1 h. 5.8 1.26 5591.5 4428.0 104.8 33 1 29 <1 7 2 H. 5.7 1.35 5411.0 3996.0 101.7 35 1 28 2 10 40 ° C for 3 h. 5.8 1.25 5414.0 4327.0 99.6 30 <1 22 <1 8 30 ° C for 3 h. 5.9 1.26 5328.0 4228.0 98.6 22 <1 19 <1 4

ppm: parts per million ach: acetaldehyde D: polydispersity act: acetone F .: Fluorescent pro: propionaldehyde j.t .: indicated durability meth: methanol

h: month form: formaldehyde

Claims (18)

Claims A sealed, pharmaceutically acceptable container which, under vacuum or in an inert atmosphere, has a H0 (CzH40) b (C3He0) _{a (C2} H40) IOH (I) block copolymers (in which a is an integer with which the (ΟβΗβΟ) hydrophobe molecular weight of 950 to 4000 Daltons, and b is an integer with which the (C2H-10) hydrophilic moiety (50-95% w / w of the copolymer) contains a sterile injectable aqueous solution. The container of claim 1, wherein the hydrophobic moiety has a molecular weight of 1200-3500 Dalton. The container of claim 2, wherein the hydrophobic moiety has a molecular weight of about 1750 Daltons and the total molecular weight of the block copolymer is about 8400 Daltons. Dalton. 4. A container according to any one of claims 1 to 5, wherein the block copolymer is substantially free of any molecule having a molecular weight greater than 15,000 Daltons. The container of claim 4, wherein the amount of molecules having a molecular weight greater than 15,000 Daltons is less than 1%. The container of claim 5, wherein the molecule having a molecular weight greater than 15,000 Daltons is less than 0.5%. 7. A container according to any one of claims 1 to 6, wherein the block copolymer has a polydispersity value of less than 1.4. The container of claim 7, wherein the block copolymer has a polydispersity of less than 1.3. The container of claim 8, wherein the block copolymer has a polydispersity value of less than 1.2. The container of claim 9, wherein the block copolymer has a polydispersity of less than 1.1. 11. A container according to any one of claims 1 to 6, wherein the block copolymer is present in an amount of 135-165 mg / ml of solution volume. The container of claim 11, wherein the amount of block copolymer is about 150 mg / mL of solution volume. 13. A container according to any one of claims 1 to 6, wherein the pH of the solution is about 6. you 14. A container according to any one of claims 1 to 6, wherein the solution is buffered with citrate buffer. The container of claim 14, wherein the concentration of citrate buffer is 0.005 M to 0.05 M. The container of claim 15, wherein the concentration of citrate buffer is about 0.01 M. 17. A container according to any one of claims 1 to 6, wherein the solution is substantially isotonic with human blood serum. 18. A container according to any one of claims 1 to 6, wherein the inert atmosphere is nitrogen gas.