SI9300545A - Stable pharmaceutical formulation of a polyoxypropylene/polyoxyethylene block copolymer - 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

THE WELLCOME FOUNDATION LIMITED

Stable pharmaceutical preparation of polyoxypropylene / polyoxyethylene block copolymer

The present invention relates to a stable pharmaceutical preparation of a polyoxypropylene / polyoxyethylene block copolymer.

Some surfactant polyoxypropylene / polyoxyethylene block copolymers have been found to have beneficial effects in veterinary and human medicine. In particular, 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 perfusion media. These uses are described in U.S. Pat. 3,641,240, 4,801,452, 4,873,083, 4,879,109, 4,837,014, 4,897,263, 4,937,070, 4,997,644, 5,017,370, 5,028,599, 5,030,448, 5,032,394, 5,039,520, 5,041,288, 5,047,236, 5,064, 788, 5,807, 549, 5,078, 988, 5,071,649, 5,078, 988, 5,807, 549, 580, 1580, 1571 incorporated herein by reference.

Surfactant copolymers are effective in circulating disorders when pathological hydrophobic interaction between cells and / or molecules is present. These interactions are thought to be caused by 1) higher than normal fibrinogen concentration, 2) formation of intravascular or topically soluble fibrin, especially high molecular weight fibrin, 3) increased friction in the microvasculature, or 4) mechanical or chemical trauma to components blood. These disorders lead to an increase in pathological hydrophobic interactions of blood components such as cells and molecules. Fibrin, especially soluble fibrin, is thought to increase cell adhesion to one another, significantly increase friction in small blood vessels, and increase blood viscosity especially at low shear rates. The effects of surfactant copolymers are thought to be essentially lubricating effects because they reduce the friction caused by adhesion.

Commercially available surface-active polyoxypropylene / polyoxyethylene block copolymers generally contain antioxidants. In particular, the preparation of poloxamer 188, which can be purchased from BASF (Parsippany, New Jersey, USA), contains BHT (butylated hydroxytoluene). This antioxidant is not standardized for pharmaceutical use. In addition, antioxidants tend to be hydrophobic and insoluble in aqueous medium, and some may present toxicity problems. This is clearly undesirable in the medicine solution for injection. Therefore, it is an object of the present invention to provide an aqueous solution of a block copolymer substantially free of such antioxidants.

The absence of antioxidant in block copolymer solutions tends to result in their oxidation and degradation. This leads to molecules with a shorter chain and by-products such as organic acids (eg acetic acid), resulting in a decrease in the pH of the solution to 4 or even lower. Furthermore, the degradation of the copolymer was observed to be faster and more widespread, the lower the pH. Therefore, it is an object of the present invention to provide a stable aqueous solution of a block copolymer.

EP-A-103290 describes aqueous pharmaceutical preparations of polyoxypropylene and polyoxyethylene, adjusted to a physiologically acceptable pH, preferably from 6 to 8, with the addition of electrolytes and buffers. However, the pharmaceutical preparation of the block copolymer of polyoxypropylene / polyoxyethylene is not described, nor is any of the above mentioned defects related to such a polymer described or indicated. Similarly, in U.S. Pat. No. 4,938,961 describes an aqueous solution of polypropylene glycol, but no mention of block copolymer solutions of polyoxypropylene / polyoxyethylene.

It is a further object of the present invention to provide an aqueous solution of a polyoxypropylene / polyoxyethylene block copolymer suitable for injection, in particular intravenous injection.

The present invention is therefore a sealed pharmaceutically acceptable container containing, in a vacuum or in an inert atmosphere, a sterile aqueous injection solution of a block copolymer of formula (I)

HO (C ₂ H ₄ O) _b (C ₃ H ₆ O) _a (C ₂ H ₄ O) _b H (I) where a is such an integer that it has the hydrophobic represented by (C ₃ H ₆ O) , a molecular weight of from 950 to 4000 daltons, preferably about 1200 to 3500 daltons, and b such that the hydrophilic moiety represented by (C ₂ H ₄ O) represents from 50 to 95% by weight of the copolymer, wherein the solution is essentially antioxidant free and is purified at pH 5.5 to 6.5.

A preferred block copolymer of formula (I) is wherein the molecular weight of the hydrophobic (C ₃ H ₆ O) is about 1750 daltons and the total molecular weight of the copolymer is about 8400 daltons. One particular example of such a block copolymer is one referred to as poloxamer 188 (BASF, Parsippany, New Jersey, USA). Discussion of the structure of poloxamers and poloxamine block copolymers can be found in Schmolka, IR A Review of Block Polymer Surfactants, J.AM. OIL CHEMISTS SOC., 54: 110-116 (1977), which is incorporated herein by reference.

The commercially available sources of poloxamer 188 are said to have a molecular weight of about 8400 daltons. In fact, the block copolymer is composed of molecules with molecular weights from less than 3,000 daltons to over 20,000 daltons. The molecular diversity and distribution of commercial poloxamer 188 molecules can be demonstrated by the broad broad primary and secondary spots identified using gel permeation chromatography as described in WO 92/16484.

High molecular weight components, i.e. Components with a molecular weight exceeding 15 kDalton present in commercially available poloxamer 188 are typically up to 3% by weight of block copolymer or even more. Such significant amounts can cause undesirable side effects when clinically using block copolymer. In particular, these components have a longer elimination phase half-life than most block copolymers and thus accumulate in the plasma and kidney. In addition, high molecular weight components may be responsible for activating the complement system. Thus, it is preferred that the block copolymer useful in the present invention is free, at least to a considerable extent, i.e. less than 1% by weight, preferably 0.5 or 0.2% by weight, of molecules with a molecular weight exceeding 15 kDalts.

A standard measure of the molecular weight distribution of a polymer is its polydispersity. They refer to this and are described in WO 92/16484, the contents of which are incorporated herein by reference. In short, polydispersity 1.0 means a polymer in which all molecules have the same molecular weight. A typical polymer may have a polydispersity of from 2 to

5. The block copolymer of polyoxypropylene / polyoxyethylene for use in the present invention preferably has a polydispersity of less than 1.4, preferably 1.3 or 1.2 or even 1.1.

The surface-active block copolymer can be formed by condensation of ethylene oxide and propylene oxide at elevated temperature and pressure in the presence of a basic catalyst. However, here is a statistical variation in the number of monomer units that combine to form a polymer chain in each copolymer. The molecular weights given are approximations of the average mass of the copolymer molecule in each preparation. A more detailed discussion of the preparation of these copolymers is in U.S. Pat. No. 2,674,619, which is incorporated herein by reference. Preferred block copolymer forms, i.e., forms which are free of any significant amount of molecules with a molecular weight exceeding 15 kDalton or having a polydispersity of less than 1.4 can be obtained by the method described in WO 92/16484.

Certain commercially available block copolymers, such as poloxamer 188, may be in an antioxidant-containing form. Prior to use in the present invention, the antioxidant must be removed from the copolymer, e.g. by filtering or by any other known means. Preferably, the block copolymer is obtained in a form that is substantially free of 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 injection solution was puffed at the desired pH using buffer. Examples of such buffers are citrate (eg sodium citrate / citric acid). The concentration of the buffer, especially the citrate buffer, should preferably be from 0.005 to 0.05 M, in particular about 0.01 M.

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

The aqueous solution for injection preferably has both the tonicity and the blood serum of the patient to avoid undesirable side effects. If the tonicity of an aqueous solution for injection needs to be increased, then an essentially isotonic solution can be obtained by including a pharmaceutically acceptable agent capable of raising the tonicity of the solution to the required level. Examples of such agents are known and include dextrose and sodium chloride and mixtures thereof.

The aqueous solution for injection may be provided in sterile form by filtration or by av5 cyclization.

The formulation of the aqueous solution for injection and its filling into pharmaceutically acceptable containers is preferably carried out according to known methods, where the conditions are designed to minimize oxygen in the formulation solution or in the empty space.

Examples of pharmaceutically acceptable containers are plastic and glass containers, such as vials, ampoules and bottles. The containers may optionally be colored as amber to reduce the exposure of the aqueous solution to UV light and possible decomposition. On the other hand, the containers can be colorless but packed in opaque cartons. Preferably, the solution for injection is in an inert nitrogen atmosphere.

The surfactant copolymer can be used to treat circulatory disorders that cause or cause pathological hydrophobic interaction of blood components. Examples of such disorders are heart attack, stroke, bowel or other tissue infarction, malignancy, adult respiratory distress syndrome (ARDS), diffuse intravascular coagulation (DIC), diabetes, unstable angina, hemolytic uremic syndrome, red blood cell fragmentation syndrome, fever stroke. retained fetus, eclampsia, malignant hypertension, sickle cell disease, burns, crushes, fractures, traumatic shock, major surgery, sepsis, bacterial, parasitic, viral and rickshaw infections that accelerate activation of the coagulation system, central nervous system trauma, and during and immediately after any major surgery.

The surfactant copolymer is also effective in increasing collateral circulation to intact tissues with compromised blood supply. Such tissues are often adjacent to areas of vascular occlusion. The mechanism appears to reduce pathological hydrophobic interactions in small blood vessels. Circulatory disorders in which surface-active copolymers are effective are brain thrombosis, cerebral embolus, heart attack, unstable angina, temporary cerebral ischemic attacks, intermittent claudication of the feet, plastic and reconstructive surgery, balloon angioplasty, surgery, peripheral surgery using a vascular garter. The copolymer can also be used to preserve organs for transplantation.

The aqueous block copolymer solution for injection may be administered to a patient by bolus injection or preferably by infusion. A favorable site for administration will usually be the peripheral vein.

A bolus injection usually involves giving 2 minutes. The infusion is usually performed with a solution contained in an infusion bag or bottle or an electrically powered infusion pump. The solution may be administered from an infusion bag or bottle to a patient by gravity dosing or by using an infusion pump.

The effective amount of block copolymer for the treatment of a patient with circulatory disorder will, of course, depend on a number of factors including e.g. age and weight of the patient, treatment that requires the right conditions, route of administration and will ultimately be at the discretion of the treating physician. However, it is possible that an effective amount in the range of 0.2 to 3.0 g / kg, preferably 1.5 to 2.5 g / kg body weight, will generally be administered to the patient from 1 to 48 hours.

The following examples are intended to illustrate the present invention.

EXAMPLE 1

For a batch size of 5000 liters, we use the following formulation and manufacturing process, where nitrogen protection is always used.

to the batch

poloxamer 188, NF ¹ 750,00 kg sodium chloride, USP 15.40 kg sodium citrate (dihydrate), USP 11,90 kg citric acid anhydrous, USP 1,83 kg water for injection, USP q.s. together 5000,01

1. Collect approximately 4000 1 pre-heated water for injection (70 ° to 80 ° C) into a suitable container (container No. 1). Collect an additional 10001 pre-heated water for injection (70 ° to 80 ° C) into another container (container No 2).

2. Flush the water in both containers with filtered nitrogen gas. Cool to room temperature with constant flushing with filtered nitrogen gas.

3. Dissolve citric acid, sodium citrate and sodium chloride in water, flushed with nitrogen in vessel no. Continue flushing with filtered nitrogen gas.

4. Fill the empty space with filtered gas nitrogen and stop flushing with nitrogen. Slowly add block copolymer to the solution. Stir until dissolved. Note: Continue filling the empty space with filtered nitrogen gas while stirring.

5. Add enough water for injection previously rinsed with nitrogen (from container # 2) to bring the batch to a final volume, and stir.

6. Filter the solution through a membrane filter, 0.45 μτη or equivalent, into a suitable, clean, nitrogen-flushed tank.

7.

Under clear conditions, it fills approximately 500 ml of solution into pre-washed, 6508 ml type 1 silica bottles.

8. Under clear conditions, apply suitable caps to bottles without inserting them into bottles.

9. Apply the vacuum to an empty space and insert the caps into the filled bottles.

10. Apply fillings.

11. Finally sterilize the product.

12. Cool the product to room temperature, then stir to evenness.

13. Store bottles in individual cartons to protect the product from light.

The quantities of the above components in the preparation in ml are as follows:

per ml poloxamer 188, NF ¹ sodium chloride, USP sodium citrate (dihydrate), USP anhydrous citric acid, USP water for injections, USP total

150.0 mg 3.08 mg 2.38 mg 0.366 mg

q.s.

1.0 ml ¹ Contains less than 0.2% of molecules in molecular weight above 15 kDalton and is in this form.

The aqueous injection solution thus obtained is a clear, colorless solution, free from particulate matter, mist or inhomogeneity, and is stable as demonstrated by the following data:

poloxamer 188 (PPM)

Storing PH D Mw Mn % l.s. ach act dec met form during storage 5.8 1 21 5718.0 4713.0 99 3 25 <1 21 <1 2 UV: 7 days 5.8 not done. 98.4 25 3 24 <1 2 14 days 5.8 not done.— 99.1 20 - » J 20 <1 2 Fluoride: 7 days 5.8 not done— 100.3 24 7 25 <1 1 14 days 5.8 -—- not done-— 99.0 19 7 19 <1 1 50 ° C for 1 month 5.8 1.24 5438.0 4408 0 101.6 22 <1 19 <1 4 4 months5.8 1.24 5418.0 4369.0 98.3 Λ -> J J 1 29 <1 6 40 ° C 4 months 5 7 1.26 5437.0 4326.0 98.6 36 <1 JO <1 5 30 ° C 4 months 5.6 1.25 5429.0 4354.0 99.2 35 1 33 <1 5

PPM: millionths D: polydispersity (Mw / Mn) N / A: not available Fluorine: fluorescent

hp: labeled ach concentration: acetaldehyde act: acetone pro: propionaldehyde meth: methanol form: formaldehyde

EXAMPLE 2

Repeat the process of Example 1 with batch size 200 1 using the following composition and collecting 1601 in container no. 1 and 401 in container no. 2.

poloxamer 188, NF ¹ 30,00 kg sodium chloride, USP 0,616 kg sodium citrate (dihydrate), USP 0,476 kg anhydrous citric acid, USP 0,0732 kg water for injection, USP qs

a total of 200.01

The aqueous solution for injection obtained was similar in physical appearance to that obtained in Example 1. The following stability data were obtained.

Poloxamer 188 (PPM) degradation products

Storage pH D Mw Mn% l.s. ach act pro met form at contract-

breathing 5.8 1.24 5550.0 UV: 7 days 5.7 1.28 5764.5 14 days 5.9 1.29 5789.0 Fluoride: 7 days 5.8 1.29 5852.0 14 days 5.9 1.29 5873.0 50 ° C for 1 month 5.8 1.26 5591.5 2 msseca5.7 1.35 5411.0 40 ° C 5.8 1.25 5414.0 30 ° C 5.9 1.26 5328.0

4482.0 99.8 32 <1 11.0 <1 <1 4509.5 99.7 23 4 24 1 3 4498.0 98.8 22 7 23 1 1 4535.5 99.2 24 9 23 2 3 4545.5 98.1 25 12 25 2 4 4428.0 104.8 33 1 29 <1 7 3996.0 101.7 35 1 28 2 10 4327.0 99.6 30 <1 22 <1 8 4228.0 98.6 22 <1 19 <1 4

PPM: millionth D: polydispersity (Mw / Mn) N / A: not available Fluorine: fluorescent HP: labeled ach: acetaldehyde act: acetone pro: propionaldehyde meth: methanol form: formaldehyde

Claims (18)

PATENT APPLICATIONS A sealed pharmaceutically acceptable container, characterized in that it contains, in a vacuum or in an inert atmosphere, a sterile aqueous injection solution of a block copolymer of formula (I) HO (C ₂ H ₄ O) _b (C ₃ H ₆ O) _a (C ₂ H ₄ O) _b H (I) where a is such an integer that it has the hydrophobic represented by (C ₃ H ₆ O) , a molecular weight of from 950 to 4000 daltons, and b being such an integer that the hydrophilic moiety represented by (C ₂ H ₄ O) represents from 50 to 95% by weight of the copolymer, the solution being substantially free of antioxidant and is fluted at pH 5.5 to 6.5. Container according to claim 1, characterized in that the molecular weight of the hydrophob is from 1200 to 3500 daltons. Container according to claim 2, characterized in that the molecular weight of the hydrophob is about 1750 daltons and the total molecular weight of the block copolymer is about 8400 daltons. Container according to any one of the preceding claims, characterized in that the block copolymer is substantially free of any molecule with a molecular weight exceeding 15000 daltons. Container according to claim 4, characterized in that the amount of molecules with a molecular weight above 15000 daltons is below 1%. Container according to claim 5, characterized in that the amount is less than 0.5%. Container according to any one of the preceding claims, characterized in that the block copolymer has a polydispersity below 1.4. Container according to claim 7, characterized in that the polydispersity is less than 1.3. Container according to claim 8, characterized in that the polydispersity is less than 1.2. Container according to claim 9, characterized in that the polydispersity is less than 1.1. Container according to any one of the preceding claims, characterized in that the block copolymer is present in an amount of 135 to 165 mg / ml solution. Container according to claim 11, characterized in that the amount is about 150 mg / ml of solution. 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, characterized in that the solution is purified using citrate as a buffer. Container according to claim 14, characterized in that the concentration of citrate buffer is from 0.005 to 0.05 M. 16. A container according to claim 15, characterized in that the concentration is about 0.01 M. Container according to any one of the preceding claims, characterized in that the solution is substantially isotonic with human blood serum. A container according to any one of the preceding claims, characterized in that the inert atmosphere is nitrogen. 23301-X-93 / Li For THE WELLCOME FOUNDATION LIMITED: SUMMARY Stable pharmaceutical preparation of polyoxypropylene / polyoxyethylene block copolymer A sealed pharmaceutically acceptable container containing, in a vacuum or in an inert atmosphere, a sterile aqueous injection solution of a polyoxypropylene / polyoxyethylene block copolymer, the solution being substantially free of antioxidant and sealed at pH 5.5 to 6.5.