HK1064954B - Clear propofol compositions - Google Patents

Description

Clear and stable propofol composition

Technical Field

The present invention relates to a process for the preparation of a clear sterile anaesthetic composition suitable for parenteral administration of propofol.

Technical Field

Propofol (2, 6-diisopropylphenol) is an intravenous anaesthetic characterized by a short recovery time. It has the desirable properties that after intravenous administration, the anesthetic effect starts and ends rapidly and with minimal accumulation over long term administration.

Although propofol is preferred as an anesthetic, it has been a significant challenge to formulators since its invention because of its insolubility in water. Initially, it was formulated as a 1% aqueous solution containing the nonionic surfactant Cremophor EL as a solubilizing agent. However, Cremophor EL is implicated in some adverse reactions, including anaphylactoid reactions, when administered intravenously. Subsequently, the anesthetic was formulated as an oil-in-water emulsion comprising 1% (w/v) propofol and 10% (w/v) soybean oil and 1.2% (w/v) purified lecithin.

However, lipid-based emulsions suffer from several limitations as follows.

Improper storage leads to poor physical stability.

Toxic free fatty acids are produced during storage.

Embolism may result due to the larger oil droplet size.

Pain caused by injection (oily in the formulation)

Online microbial filters cannot be used in medicine.

Since the product has a milky appearance, the particles of impurities cannot be visually inspected before application.

Selective mixing with only a few injectable products before administration.

In the case of administration, strict aseptic techniques must be followed, since emulsion systems are very susceptible to bacterial growth.

During maintenance of anaesthesia, the infusion tube needs to be replaced frequently, since the product in the infusion tube can support the growth of bacteria.

Lecithin is included as an emulsifier. If derived from animal sources, it may cause allergic reactions in some patients.

Increase of plasma phospholipid concentration, decrease of triglyceride clearance leading to hypertriglyceridemia, hypercholesterolemia.

Before autoclaving, the product cannot be filtered through a 0.22 μm filter.

The inherent limitations of emulsion formulations as described above can be overcome by removing the vegetable oils and phospholipids from the formulation. Since propofol is an oily liquid, insoluble in water, it is possible to develop propofol formulations (excluding vegetable oils and phospholipids) for this type of parenteral use if solubilizers are used to render propofol aqueous soluble.

WO00/78301 discloses intravenous anesthetic compositions comprising propofol and a poloxamer as surfactants. Optionally, it may comprise at least one surfactant selected from: solutol HS15, lecithin, Labrasol, polyoxy-10-oleyl ether, Tween, ethanol and polyethylene glycol. The composition is prepared in the form of a microemulsion having a particle size below 100nm and can be sterile filtered.

WO01/64187 also discloses similar intravenous anesthetic compositions comprising propofol and a poloxamer. This invention defines the type of polymer that can be used, i.e., a propylene oxide fraction of at least 2000D and an ethylene oxide fraction of at least 40% (w/w). The effect of the added electrolyte (sodium chloride) on the stability, pH and hydrodynamic radius of the micelle has been discussed. However, the stability of the active ingredient propofol is not considered in both of the above patents. Poloxamer and phenol are reported to be contraindicated for drug compatibility. (reference Martindale32^ndedition, pg.1326), and it is therefore questionable whether such compositions can maintain propofol activity for extended periods of time.

The main object of the present invention is to develop a clear, stable, sterile aqueous propofol composition which overcomes the disadvantages of the prior art formulations and the disadvantages of the prior art.

Summary of The Invention

The present invention relates to a clear stable anaesthetic composition suitable for parenteral administration comprising propofol (1 mg/ml to 20mg/ml of the composition), d-alpha Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS), water, with or without parenterally acceptable conventional additives, wherein the ratio of propofol to TPGS is maintained at 1: 10 (weight) and the content of TPGS in the composition is 1% to 20% (weight/volume).

The anesthetic composition of the present invention is prepared by a process comprising

a) Dissolving TPGS in water to obtain a TPGS solution;

b) adding propofol to the TPGS solution with mixing to obtain an anesthetic composition;

c) if desired, the additive may be added to water, the TPGS solution or the resulting anesthetic composition;

d) compensating the volume with water to obtain a desired level of propofol in the anesthetic composition;

e) filtering the composition obtained at the end of step (d) with a filter of 2 μm and 0.2 μm;

f) filling a container, such as a vial, ampoule, plastic container, with the filtrate obtained at the end of step (e) after purging with nitrogen, and then sealing the filled container;

g) autoclaving the sealed container filled with the filtrate.

Detailed Description

In developing propofol anaesthetic compositions for the above purposes, it has been found that some of the hydrophobic therapeutic drug is dissolved in alpha-tocopherol, an oily substance and that the alpha-tocopherol solution is emulsified using TPGS as an emulsifier (reference: WO 98/30205). In an attempt to avoid oily compositions, it was found after extensive testing that by using sufficiently large amounts of TPGS, the hydrophobic propofol anaesthetic could be dissolved in water to give a composition suitable for parenteral administration.

WO98/30205 fully discloses ethanol free self emulsifying drug delivery systems. The pharmaceutical compositions of the present invention are typically prepared by dissolving the therapeutic agent in ethanol to form a therapeutic agent solution. The alpha-tocopherol is added to the therapeutic agent solution to form an alpha-tocopherol and therapeutic agent solution. The ethanol is then removed to form a substantially ethanol-free solution of alpha-tocopherol and the therapeutic agent. The substantially ethanol-free solution of alpha-tocopherol and therapeutic agent is mixed with or without water with added surfactant to create a pre-emulsion. For intravenous delivery, the pre-emulsion is homogenized into a fine emulsion.

In this delivery system, ethanol is used to solubilize the therapeutic agent and to add the large amount of alpha-tocopherol, which is necessary to solubilize the drug in solution.

TPGS is a water-soluble form of alpha-tocopherol prepared by esterifying the acidic groups of crystalline d-alpha tocopheryl succinate with polyethylene glycol 1000. TPGS is very stable and does not hydrolyze under normal conditions.

TPGS melts at 41 ℃ and has a decomposition temperature higher than 199 ℃. The solubility of TPGS in water at 20 ℃ is 20 g%. The HLB value of TPGS is about 15-19.

To dissolve TPGS in water, it is required to add TPGS to hot water. Preferably, the temperature of the water is 45 ℃ to 100 ℃.

TPGS does not decompose when exposed to oxygen, heat, light or oxidizing agents. It is not stable to alkali.

In preparing the compositions of the present invention, extensive testing has been conducted to find that the oil-soluble anesthetic propofol can be dissolved in water with the aid of TPGS without the use of any tocopherol or any oil phase, and if larger amounts of TPGS are used, a propofol-containing dissolved product is obtained.

The compositions of the present invention are stable products when stored under temperature controlled conditions, i.e., refrigerated storage.

The propofol content of the compositions of the present invention is from about 1mg/ml to about 20mg/ml, preferably from about 2mg/ml to about 20mg/ml, more preferably 10 mg/ml.

The amount of TPGS in the compositions of the invention is from about 10mg/ml to about 200mg/ml, preferably from about 100mg/ml to about 150mg/ml, more preferably 100 mg/ml.

The present invention provides clear, stable, sterile aqueous compositions suitable for parenteral administration without the need for any conventional additives.

However, in other embodiments of the invention, conventional additives may be added to the aqueous solution in parenteral dosages at any stage of preparation, if desired.

Conventional additives which are parenterally acceptable are selected, at conventional dosage levels, from, for example, buffers, tonicity modifying agents, preservatives and antioxidants.

Any buffer for parenteral use may be used in the compositions of the present invention, which is selected from buffers such as phosphate buffers, glycine buffers, citrate buffers or mixtures thereof. As long as a buffer is used, a phosphate buffer is preferred. Phosphate buffers of various combinations of sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid, sodium hydroxide may be used to obtain the desired pH of the composition. Preferably the pH of the final composition ranges from 4.0 to 8.0.

The compositions of the present invention may also include a tonicity modifier to render the composition isotonic with blood. The tonicity modifier is selected from a parenterally acceptable compound such as dextrose, sodium chloride, mannitol, glucitol, glycerol, propylene glycol, or mixtures thereof. Glycerol is particularly preferred as a tonicity modifier, used at a concentration of 2 to 3% (weight/volume) of the composition. More preferably, the glycerol concentration in the final composition is 2.25% (weight/volume).

The preservative used in the composition of the present invention is selected from a parenterally acceptable compound such as edetate disodium, benzyl alcohol, sodium benzoate or mixtures thereof. Disodium edetate is particularly preferred as a preservative, used at a concentration in the range of 0.0025 to 0.01% (w/v) of the composition.

The compositions of the present invention also comprise an antioxidant selected from the group consisting of parenterally acceptable compounds such as ascorbyl-6 palmitate, ascorbic acid and ascorbate. One of the advantages of TPGS is that it can act as an antioxidant itself, without the need for the addition of other antioxidants. In light of the foregoing disclosure, it will be apparent to those skilled in the art that various modifications, additions may be made without departing from the spirit and scope of the disclosure. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it can be practiced within the full scope of the appended claims.

Example (b):

the invention will now be illustrated by way of examples. The examples are intended to illustrate the present invention and do not limit the scope of the present invention.

All materials used in this example were of parenteral grade. The equipment used is conventional. The entire process is carried out in a controlled environment. And performing nitrogen sealing after processing one batch.

The following starting materials were used in the examples

a) Propofol produced by Cilag AG

b) TPGS produced by M/s.Eastman Chemical Ltd. following the United states national Pharmacopeia (USNF) regulations

c) The water used complies with the Indian pharmacopoeia 'water for injection' specifications

d) The glycerol used complies with the Indian pharmacopoeia specifications

e) Disodium edetate used complies with the Indian pharmacopoeia specifications

f) The potassium dihydrogen phosphate used complies with the United states pharmacopoeia (USNF) specifications

g) The disodium hydrogen phosphate used complies with the Indian pharmacopoeia specifications

h) Commercial product using Propofol (Diprivan) -propofol emulsion (10mg/ml)

Example I:

TPGS was melted and 20g of the melted TPGS was added to boiling water (170 ml). Stir until TPGS is completely dissolved. Propofol (2g) was added to the TPGS solution with stirring. The product was stirred until a clear solution was obtained. The volume was made up to 200ml with water. Filtration was carried out using a 2 μm prefilter and a 0.22 μm membrane filter. The product was filled into sterile, non-hot glass flasks under a laminar flow nitrogen blanket. The flask was closed with a fluoro-rubber stopper and closed with an aluminum closure. The filled and sealed flask was autoclaved for 20 minutes at 121 ℃.

Stability data for the product of example I at recommended storage conditions at temperatures of 2-8 deg.C

Period of time	Appearance of the product	Propofol content
			Initial	Clear yellowish liquid	101.63％
6 months old	Clear yellowish liquid	100.42％
			9 months old	Clear yellowish liquid	99.47％

The stability data above show that the product prepared in example I is suitable for commercial markets.

Example II

Example II the same as example I, but with propofol dissolved, glycerol (4.5g) was added.

Example III

Example III the same as example II, except that disodium edetate (0.011g) was dissolved in boiling water prior to the addition of TPGS.

Example IV

Example IV is the same as example I, but using phosphate buffer at pH 5.5 instead of water.

Phosphate buffer with a pH value of 5.5 was prepared by mixing 96.4ml of "solution I" and 3.6ml of "solution II".

1) Solution I-13.61 g of monopotassium phosphate are dissolved in sufficient water to make up to 1000 ml.

2) Solution II-35.81 g of disodium hydrogen phosphate are dissolved in sufficient water to make up to 1000 ml.

Example V:

same as example I, but using 16g TPGS instead of 20 g. The resulting product was cloudy, indicating that propofol was not completely dissolved.

Example VI:

toxicity studies were performed in mice on the propofol compositions prepared in example I.

Single dose toxicity study in mice

Feedstock and method

The test system comprises: using slave Bharat Serums&Female Swiss white mice weighing 20-22g obtained from mice with the vaccins Ltd (BSVL) animal house were studied. Supplying animal with standard food and Aquaguard in random amount^TMAnd (3) water.

Test raw materials: the propofol composition prepared in example I (10mg/ml) was administered intravenously.

Comparing raw materials: the commercial Propofol-propofol emulsion (10mg/ml) was used for intravenous administration.

All animals (8 per group) were observed for signs of clinical toxicity, if any, and mortality during 72 hours. Percent mortality was calculated for all doses. The results are given in the following table.

Dosage (mg/kg body weight)	Mortality of the sample of example I%	Mortality of Propofol%
			35	0	0
40	25	25
			45	37.5	37.5
50	50	50

And (4) observation:

the group receiving the propofol composition of example I exhibited similar signs of toxicity compared to the group receiving propofol.

Example VII

The propofol compositions prepared in example I were subjected to efficacy studies in mice.

Feedstock and method

The test system comprises: using slave Bharat Serums&Female Swiss white mice weighing 20-22g obtained from mice with the vaccins Ltd (BSVL) animal house were studied. Supplying animal with standard food and Aquaguard in random amount^TMAnd (3) water.

Test raw materials: the propofol composition prepared in example I (10mg/ml) was administered intravenously at a dose of 35 mg/kg.

Comparing raw materials: the commercial Propofol-propofol emulsion (10mg/ml) was administered intravenously at a dose of 35 mg/kg.

All animals (8 per group) were observed for time to admission to anesthesia and time to recovery from anesthesia. The observations were as follows:

mean induction time		Average recovery time
				Example I	Propofol	Example I	Propofol
4.2 seconds	4.1 seconds	8.6 minutes	7.9 minutes

The stability, toxicity and efficacy studies of example I demonstrate that the compositions of the present invention are stable, overcoming all of the disadvantages of the emulsion formulations discussed above, and are comparable in toxicity and efficacy to propofol.

The invention has the advantages that:

the present invention provides a clear, sterile anesthetic composition that overcomes all of the previously discussed disadvantages of emulsion formulations and results in a composition having a number of advantages, some of which are as follows:

i. the composition is clear, can be visually inspected prior to administration and can be administered using an in-line microbial filter.

The composition is free of phospholipids. Plasma phospholipids therefore do not interfere with parenteral administration of the composition.

The composition does not cause any change in triglyceride clearance

The composition may be mixed with any conventional diluent prior to administration.

Claims (12)

1. A clear and stable anaesthetic composition suitable for parenteral administration which comprises the following components:

1mg/ml to 20mg/ml propofol;

1% to 20% w/v d-alpha tocopheryl polyethylene glycol 1000 succinate wherein the ratio of propofol to d-alpha tocopheryl polyethylene glycol 1000 succinate is 1: 10 w/v; and

water;

with or without parenterally acceptable additives.

2. The clear stable anaesthetic composition suitable for parenteral administration as claimed in claim 1 wherein propofol is present at about 10mg/ml of the composition.

3. A clear stable anaesthetic composition suitable for parenteral administration as claimed in any of claims 1 to 2 wherein d-alpha tocopheryl polyethylene glycol 1000 succinate is present in an amount of from 100mg/ml to 150mg/ml of the composition.

4. A clear stable anaesthetic composition suitable for parenteral administration as claimed in any of claims 1 to 2 wherein the parenterally acceptable additives are selected from buffers, tonicity modifying agents, preservatives and antioxidants.

5. A clear stable anaesthetic composition suitable for parenteral administration as claimed in claim 4 wherein the buffer used is selected from a parenterally acceptable buffer selected from a phosphate buffer, a glycine buffer, a citrate buffer or a mixture thereof.

6. A clear stable anaesthetic composition suitable for parenteral administration as claimed in claim 4 wherein the tonicity modifying agent used is selected from a parenterally acceptable compound selected from glucose, sodium chloride, mannitol, glucitol, glycerol, propylene glycol or a mixture thereof.

7. A clear stable anaesthetic composition suitable for parenteral administration as claimed in claim 6 wherein the tonicity modifying agent used is glycerol.

8. A clear stable anaesthetic composition suitable for parenteral administration as claimed in claim 6 wherein the tonicity modifying agent used is propylene glycol.

9. A clear stable anaesthetic composition suitable for parenteral administration as claimed in claim 4 wherein the preservative used is selected from a parenterally acceptable compound selected from disodium edetate, benzyl alcohol, sodium benzoate or a mixture thereof.

10. A process for the preparation of a clear stable anaesthetic composition suitable for parenteral administration as claimed in any of claims 1 to 9 comprising:

a) dissolving d-alpha tocopheryl polyethylene glycol 1000 succinate in water to obtain a solution of d-alpha tocopheryl polyethylene glycol 1000 succinate;

b) adding propofol to said d-alpha tocopheryl polyethylene glycol 1000 succinate solution with mixing to provide an anesthetic composition;

c) compensating the volume with water to obtain a desired propofol level in the anesthetic composition;

d) filtering the composition obtained in step (c) with a 2 μm and 0.2 μm filter;

e) filling the container with the filtrate obtained in step (d) after purging with nitrogen, and then sealing the filled container;

f) autoclaving the sealed container filled with the filtrate.

11. The method according to claim 10, further comprising the step of adding said additive to water, d-alpha tocopheryl polyethylene glycol 1000 succinate solution or the formed anesthetic composition between steps (b) and (c).

12. The method according to claim 10, wherein the container is a vial, ampoule or plastic container.