HK1135029B - Stable and ready-to-use oil-in-water propofol microemulsion - Google Patents

Description

Stable ready-to-use oil-in-water propofol microemulsion

Technical Field

The present invention describes an injectable ready-to-use anaesthetic pharmaceutical composition for parenteral administration which is an oil-in-water microemulsion containing propofol as the active agent, the dispersed hydrophobic particles of which are smaller in size and more stable, making it a clear-looking microemulsion.

Background

The active drug propofol, the active drug of the present invention, has the assigned chemical name 2, 6-bis- (1-methylethyl) -phenol. Its preparation is described, for example, in patents US2,831,898 and US 4,447,657, and its anesthetic and sedative/hypnotic activity in mammals is first described in patent US 4,056,635.

Contains 1% to 2% concentration (w/v)) Injectable anesthetic fat emulsion of propofol, currently marketed under the brand name. In Brazil, there is also a brand nameThe medicine of (1).

Propofol has a short-term effect, sufficient to induce and maintain general anesthesia; sedation is achieved when local surgical techniques are used; the patient receiving intensive care ventilation is calmed; and surgical and diagnostic procedures performed in intensive care units. It is usually administered as a single or repeated intravenous injection in bolus quantities or as a continuous infusion, and is rapidly cleared and metabolized from the blood. For this reason, deep anesthesia is easily controlled and recovery after patient withdrawal is often rapid.

Propofol has the property of beginning to act rapidly upon administration, largely due to its considerable lipid solubility, which makes it able to rapidly traverse the blood-brain barrier. To ensure that the rate of induction of anaesthesia is sufficiently rapid, it is of interest to administer propofol directly to the blood.

However, since body fluids are essentially composed of water, the low solubility of propofol in water has prevented the development of formulations suitable for parenteral administration.

The conventional technique for enhancing the hydrophilicity of a drug is to obtain ionized salts derived from such drug in order to render it more water soluble, thereby allowing it to release the active free base in vivo. However, the ionization of a salt depends on its pKa value, and sometimes the relationship between the physiological pH and the pKa value of the resulting salt may not be in accordance with the degree necessary for its effective distribution and absorption to be sufficient to ionize the drug.

Despite the extensive research using the above method, propofol is not suitable for this method. In such cases, the propofol containing pharmaceutical composition plays a key role in increasing the water solubility characteristics of the final product in order to provide adequate drug delivery through the bloodstream.

The most common technique for developing more adequate formulations for intravenous administration is to incorporate propofol into a pharmaceutical composition in the form of an oil-in-water emulsion in which the drug is dissolved in a dispersed phase, typically consisting of fatty acids, vegetable oils and/or triglycerides.

The propofol oil-in-water emulsion of the prior art is prepared from vegetable oil, preferably soybean oil, to which phospholipids, such as egg lecithin, are added as tensioactive agent. For example, propofol is oneEmulsions provide, often, a fat emulsion for intravenous administration as a high nutrition (hypercaloric) parenteral nutrition.

However, the constitutionThe unsaturated fatty acids of the emulsion are very susceptible to peroxidation, generating hydrogen peroxide, which may be responsible for the toxicity and carcinogenic risk of such lipid emulsions, [ hellblock HJ; et al "toxin hydroperoxides in intravenous lipidemulsiohs used in preterm infants", Pedaytrics 91, 83(1993)]. In addition, microorganisms can grow in this emulsion, leading to The occurrence of postoperative infection events [ Heldmann E et al "The association of a reactive use with a reactive wound infection rate in The wound: aretroactive study "Vet Surg 28(4), 1999; seeberger MD et al "efficiency of specific antigenic prediction for predicting pro-reactive-contacts: analysis by a quality-evaluating program using the explicit output method ". J Hosp Infect39(1), 1998; sklar GE "Propofol and silicone infectins" Ann Pharmacother 31(12), 1997]。

Thus, oil-in-water emulsions rely on the addition of preservatives to prevent oxidation of the lipids in the components. Preservatives must be used to prevent microbial growth, or extremely sterile techniques are used to avoid microbial contamination and growth in the formulation.

Several documents of the prior art show attempts to prevent or eliminate this problem.

Patents EP814787 and US 5,714,520 describe a composition containing disodium edetate in a sufficient amount to prevent microbial growth. However, the addition of disodium edetate to prevent microbial growth in the formulation is not recognized by USP (United states Pharmacopeia) standards, [ Sklar GE "Propofol and microbial infections" Ann Pharmacother 31 (12); 1521 to 1523.1997; and WO 99/39696) ].

Patent application WO 39696/99 discloses the use of sulfites, preferably sodium metabisulfite, in non-toxic doses to retard or inhibit the growth of microbial contaminants. However, such substances may cause allergic reactions.

It is important to emphasize that propofol is the drug of choice as a sedative for long-term use in bedridden patients. Thus, the large amount of oil and prolonged exposure to these oil-in-water emulsions may cause problems associated with excess lipids in the blood, resulting in elevated blood lipids. This excess lipid may exceed the ability of the patient to eliminate fat from the blood, leading to the so-called fat overload syndrome [ Lindholm M "clinical ill patents and fat formulations", Minerva antiestrol 58(10), 1992], leading to sudden elevation of triglyceride serum levels, increased blood bilirubin levels, "fatty liver", fever, hepatosplenomegaly, blood coagulation disorders and other disorders of various organs [ Haber et al, "facial load syndrome, an automatic study with evaluation of the same diagnostic pathway". Am J Clin Pathol 90 (2): 223-227.1988]. In addition, tolerance to fat may be reduced in some patients with disease, resulting in altered secondary metabolism.

Another problem relates to the excessive particle size (10) of the particles of the intravenous emulsion used in the dispersed phase³To 10⁴nm)。Very dense particles make the instability between phases greater and make the formulation very hazy. This fact hinders the visual control of the sterility of the emulsion and may lead to embolism.

The risk associated with the particle size of the emulsion can be overcome by modifying it to a microemulsion. It is known that the microemulsion preparation prepared by using a surfactant can increase sufficient drug solubility and can reduce interfacial tension.

Patent US 5,637,625 relates to a preparation containing propofol microparticles coated with a fat-free and triglyceride-free phospholipid layer. The size of such particles is between 100nm and 200 nm. The aqueous phase of the formulation consisted of glucose/phosphate buffer adjusted to pH 7.0. Although the formulation is reported to be free of oils required for microbial growth as nutrients for the microorganisms, the formulation contains sugars or other carbohydrates that facilitate microbial growth.

Patent US 6,071,974 discloses the addition of propofol to a water-miscible solvent, 2, 5-dimethylisosorbide. According to the inventors, it constitutes a relatively effective formulation compared to the current commercial formulations.

Patents US 6,623,765 and GB 2359747 disclose injectable microemulsions containing propofol and, in addition, surfactants consisting of long-chain polymers, in particular poloxamers, for the formation of micelles.

Patent US 6,743,436 discloses an injectable composition which is a propofol oil-in-water microemulsion using poloxamers as surfactants. This patent uses poloxamer as a suitable surfactant and the particle size of the microemulsion formed is 100nm or less. Furthermore, it is mentioned that the cosurfactants used are selected from: SOLUTOL HS15 (Macrogol 15Hydroxystearate), egg lecithin, LABRASOL (glyceryl polyoxycaprylate), polyoxyethylene 10 oleyl ether, Tween, ethanol and polyethylene glycol. According to this patent, poloxamer407 (0.1 to 5%) is the preferred surfactant, but poloxamer 188 is also mentioned in its examples.

However, injectable poloxamer-containing compositions exhibit limitations for large or long-term administration. These preparations are related to the lipid overload syndrome, which causes damages to patients, in particular hypertriglyceridemia and hypercholesterolemia, leading to atherosclerosis [ JonhstontP et al "patent downlink administration of HMG-CoA reductase appended administration of P-407 in C57BL/6 mic". JCardiovasc Pharmacol.34(6). 1999; johnston TP et al, "Poloxamer 407-induced thermal disorders in micro additives to be products to additives and not to matters direct effects on endothecial cells and macrogels". Medoytors Inflamm.12(3). 2003; jonhston TP "The P-407-induced murine model of dose-controlled dhyperlipidemia and atherosclerosis: a review of fines to date ". J Cardiovasc Pharmacol.43(4).2004 ].

Another propofol microemulsion is composed of a mixture of surfactants as described by Ryoo et al. [ Ryoo HK et al "Development of propofol-loaded micro-architectural delivery". Arch Pharm Res.200528 (12): 1400-1404]. In their study, Ryoo et al performed an accelerated stability test (40 ℃) for only 8 weeks involving 3 different 1% propofol microemulsions containing a surfactant/co-emulsifier mixture of Solutol/ethanol 5: 1 ratio. The microemulsions studied were prepared to contain 4, 6 and 8 wt% Solutol/ethanol 5: 1 mixtures. The graphs in the study report show that in subsequent stability tests over only 8 weeks, 2 of the 3 formulations showed an increase in particle size value to close to 100nm in one case (mixture 6%) and close to 200nm in the other cases (mixture 4%). Unless a surfactant mixture is included, the formulation is unable to maintain the desired stability of particle size.

Patent application WO2005/079758 discloses self-microemulsifiable composition matrices consisting of 2 or 4 components. The two-component matrix consists of: the first part is formed from a surfactant containing polyethylene glycol and liquid propofol containing vitamin E, and the second component, i.e. an isotonic saline carrier or glucose. The carrier is mixed with the first component during use. On the other hand, the four-component matrix is more complex and consists essentially of a surfactant containing polyethylene glycol, liquid propofol containing vitamin E, a water-miscible co-solvent, and ethanol. This document states that the matrix is stable for an undetermined period of time, but no stability test confirms the statement. One of the advantages is attributed to the fact that the present invention will make it possible to prepare formulations containing propofol at high concentrations. However, the authors did not specify the importance of increasing propofol concentration. In contrast, it is well known that high concentrations of propofol may cause side effects, in particular, for example, heart failure, metabolic acidosis and rhabdomyolysis [ De Cosmo, G et al, "Sedationin PACU: the Role of Propofol "Current Drug targets.2005.6 (7): 741].

In view of the deficiencies found in the prior art with respect to excipients used in injectable propofol compositions, there is a need to develop a ready-to-use microemulsion that is smaller and more stable, and that minimizes the side effects inherent to propofol or related to overload syndrome.

Disclosure of Invention

In this context, the present invention describes an injectable anaesthetic pharmaceutical composition comprising propofol as the active agent in the form of a very stable ready-to-use oil-in-water microemulsion having dispersed hydrophobic particles of very small size.

Surprisingly, the propofol microemulsions of the present invention are more effective in inducing and maintaining hypnosis and anesthesia than prior art propofol compositions. It is noted that the ready-to-use microemulsions according to the invention, even at half the concentration (0.5% w/v), produce an anaesthetic and hypnotic effect equivalent to that of the conventional formulations containing 1% (w/v) propofol. With lower propofol doses, the desired anaesthetic and hypnotic effects can be achieved, which minimises the risk of side effects and potential adverse effects inherent to propofol.

The microemulsions according to the present invention are therefore characterized by the fact that the final composition contains propofol in a concentration ranging from 0.1% to 5% (w/v). Preferably, propofol is in the range of 0.1 to 2% (w/v), more preferably, propofol is present in the final composition in a concentration in the range of 0.5% to 1% (w/v).

An important aspect of the ready-to-use microemulsion of the present invention resides in the fact that: the dispersed particle size is greatly reduced, comprises 1 to 100nm, more specifically 1 to 50nm, and maintains stability for at least 12 months. Because of this feature, the microemulsions of the present invention have a transparent appearance and viscosity comparable to aqueous solutions.

The microemulsions of the invention are further characterized by containing a single surfactant selected from polyethylene glycol stearates, preferably non-ionic. The general molecular formula is C₁₇H₃₅COO.(OCH₂CH₂)_nH or C₁₇H₃₅COO.(OCH₂CH₂)_n.COOC₁₇H₃₅In the range of 1 to 50% (w/v) of the final composition, preferably 5 to 20% (w/v) of the final composition.

Preferably, the microemulsion of the present invention uses SOLUTOL HS15 (Macrogol 15 hydrosystemate) as a surfactant, but this is not a limitation of the scope of the present invention. Other suitable surfactants that may be used in the present invention include polyoxyethylene (4) monostearate, polyoxyethylene (6) monostearate, polyoxyethylene (8) monostearate, polyoxyethylene (12) monostearate, polyoxyethylene (20) monostearate, polyoxyethylene (30) stearate, polyoxyethylene (40) monostearate, polyoxyethylene (50) monostearate, polyoxyethylene (100) monostearate, polyoxyethylene (150) stearate, polyoxyethylene (4) distearate, polyoxyethylene (8) distearate, polyoxyethylene (12) distearate, polyoxyethylene (32) distearate, polyoxyethylene (150) distearate.

Alternatively, the microemulsions of the present invention may contain pH adjusting agents and osmolality adjusting agents that are pharmaceutically acceptable for intravenous infusion environments. Preferred agents for these purposes are, but are not limited to, sodium hydroxide and glycerol, respectively.

The microemulsion of the invention can be sterilized by a filter membrane with the aperture of 0.22 mu m.

The route of administration of the pharmaceutical composition of the present invention is preferably intravenous. However, the formulations can also be adapted for intramuscular, subcutaneous, intradermal and spinal administration.

In one aspect of the present invention, the pharmaceutical composition obtained by the components and methods described herein provides a thermodynamically stable product with a single homogeneous phase and a transparent appearance.

Another aspect of the present invention is that the microemulsions described herein are highly stable and ready to use, even after a stability test for 12 months, their particle size remains below 50nm, unlike the closest microemulsions known in the prior art.

The microemulsions of the present invention may be prepared by conventional techniques for preparing microemulsions as described in the prior art. Preferably, the microemulsion of the present invention can be prepared according to the following steps:

(a) adding a nonionic surfactant polyethylene glycol stearate in an amount of from 1 to 50% (w/v) to the first vessel and maintaining the system under constant agitation, preferably heating to about 50 ℃ until the surfactants fuse;

(b) adding propofol to the mixture in the first vessel in an amount of from 5 to 10% of the total water used in the final composition and from 0.1 to 5% (w/v), and maintaining the system under constant agitation;

(c) providing 50-85% of the total water usage of the final composition in a second vessel with an agitation system;

(d) adding the mixture in the first container into the second container, and continuously stirring until the mixture is homogenized;

(e) adding water to the final volume of the composition, and stirring continuously until homogenization;

(f) the final composition was sterilized using a 0.22 μm filter.

Optionally, adding a pharmaceutically acceptable tonicity modifier to the mixture upon completion of step (d).

However, a pharmaceutically acceptable pH adjusting agent may be added in step (e) to bring the final pH between 5.0 and 8.5.

In addition to the above-described improvements in the physicochemical properties of the pharmaceutical compositions of the invention and the surprising increase in the anaesthetic and hypnotic effects which have been established, the microemulsions of the invention have other advantages over the known prior art compositions, such as: (i) the fact that the composition of the invention is free of lipid or lecithin derived ingredients eliminates the risk of degradation/oxidation of toxic by-products formed by these ingredients; (ii) the compositions of the present invention do not contain ingredients derived from oils and sugars, which are factors that favor the growth of microorganisms, and therefore, have little potential for contamination of the product and patient; (iii) the composition of the invention can eliminate the damage of lipid overload syndrome when being taken for a long time; (iv) because the composition of the invention has another surfactant, the damage of the lipid overload syndrome caused by long-term administration of the preparation containing poloxamer can be eliminated; (v) because the size of the particles in the composition of the invention is greatly reduced, this eliminates the associated risk of embolism; (vi) because the composition of the present invention requires only half the dosage to achieve the anesthetic and hypnotic effects required by propofol, the composition minimizes the potential side and adverse effects currently associated with the use of high doses of propofol; (vii) the microemulsion of the present invention has high stability, can be used at any time, can be stored for a long time without change of physicochemical properties, and is easy to carry and administer to patients.

Thus, the pharmaceutical compositions of the present invention enable safer and more reliable intravenous administration of propofol for short or long periods of time.

The following examples are intended to illustrate, in a non-limiting manner, the best mode of carrying out the invention and its advantages over prior art formulations.

Examples 1.1% and 0.5% preparation of propofol containing microemulsions.

One completed formulation of the present invention can be described as microemulsion 1 and microemulsion 2 formulations, with preferred propofol to excipient ratios described in table 1 below:

table 1: propofol microemulsion.

According to the invention, microemulsion 1 and microemulsion 2 were prepared as follows:

70% of the total water for injection was added to a stainless steel reactor with a stirring system. In addition, macrogol 15hydroxystearate (SOLUTOL HS 15) was added to a stainless steel vessel and heated to 50 ℃ with constant stirring to give a completely melted product. Next, 6% of the total water for injection and propofol were added to the melted surfactant with constant stirring.

The contents of the stainless steel vessel were added to a reactor containing 70% of the total water for injection, glycerol was added, and stirring was continued until complete homogenization. The pH is adjusted to a value in the range of 5.0 to 8.5 using a 1N sodium hydroxide solution originally prepared with water for injection. Water for injection was added to the final volume of the composition and the final pH was checked.

The final composition was filtered through a 0.22 μm pore size GWP 293-25 sterile membrane in an AP-15257-25 prefilter.

At the end of the process, the product is enclosed in a suitable sterile bottle.

The resulting formulation is a clear microemulsion free of contaminating particles.

Example 2 stability of the propofol microemulsion of the present invention.

Freshly prepared microemulsions 1 and 2 according to example 1 were tested to evaluate their properties. The evaluation of the particle size is the most important issue of the present invention, since the stability of this parameter is a drawback of the propofol microemulsions described in the prior art.

Particle size was monitored during a 12 month stability test (see table 2) at normal temperature conditions and during a 180 day accelerated stability test (table 3) at 40 ℃.

The results shown in tables 2 and 3 indicate that there was no significant change in particle size over the monitoring time. Even earlier samples showed particle sizes significantly smaller than the maximum 50nm established as the preferred limit of the present invention.

Table 2. effect of storage time on particle size of propofol microemulsion according to the usual conditions of long term stability test.

Table 3. effect of storage time on particle size of propofol microemulsion according to the usual conditions for accelerated stability testing.

Example 3 comparative analysis of the stability of the propofol microemulsion of the prior art and the microemulsion of the present invention.

The formulation is described in patent reference US 6,743,436 (examples 1, 5 and 6), which was chosen for comparison to illustrate the improvement in physicochemical properties achieved by the pharmaceutical composition of the invention, as the closest prior art to this new composition.

When the composition was again prepared according to the teachings of the reference patent, it was observed that the composition generally did not conform to the parameters of the microemulsion and analysis showed particle size well above the limit of 100nm (see table 4).

TABLE 4 determination of the particle size in the accelerated stability test (40 ℃ C.. + -. 2 ℃ C.).

Poloxamer as a surfactant in combination with Solutol HS15 as a co-surfactant;

poloxamer in combination with other co-surfactants than Solutol HS 15.

In contrast to these results, the composition of the invention, as observed in example 2 of the invention, is completely transparent, with a particle size that remains stable even after 12 months of stability monitoring, being well below 50 nm. This clearly demonstrates the improvement in physicochemical properties achieved by the pharmaceutical compositions of the present invention.

Example 4. sterility test of the microemulsion of the invention (microemulsion 1).

The microemulsions prepared according to the present invention in example 1 were placed in three different culture media and tested for sterility by culturing, and in each medium it was observed whether it was able to develop into colony forming units (c.f.u) and the turbidity of the medium which occurred within 14 days of culturing, under specific temperature conditions suitable for the growth of the microorganism. The media used are as follows:

table 5: culture medium for the sterility test of microemulsion 1 according to the invention.

Culture medium	Temperature of culture	Incubation time
			Pancreatin soybean broth (TSB)	25℃	14 days
Liquid thioglycolate (Thio) medium	35℃	14 days
			Peptone water	25℃	14 days

After the incubation period, no evidence of bacterial growth was observed in either medium, confirming the safety of the formulation from a sterile point of view.

Example 5: pharmacological parameter comparisons of 1% microemulsion, 0.5% microemulsion and 1% commercial emulsion were observed.

To compare the pharmacological parameters of the formulations of the invention at concentrations of 1% and 0.5% with 1% commercial emulsion: () The in vivo experiment was performed. Hypnotic and anesthetic activity was studied by intravenous infusion of 6 rats weighing 260 to 350 grams. Animals were anesthetized by ether inhalation and then placed in a supine position. The anterior cervical region was dissected and the internal jugular vein was dissected. Will chargeA heparin-filled catheter was inserted through the subcutaneous cell tissue to the posterior cervical region, securing it to the skin. This method can only be performed when the animals are fully recovered (+/-60 min) from ether anesthesia. The propofol formulation was filled into a 40 μ L/min volume infusion pump (b.braun) over a 1 hour period. Hypnotic and anesthetic latencies were determined by analyzing the time intervals between the initiation of drug infusion and loss of postural reflexes and lack of response to painful stimuli (pressure on the skin in the hindfoot flat area), respectively. The results obtained are shown in table 6, as follows:

table 6: observation of commercial 1% isopropyl alcohol emulsion (w/v) ()) Comparison of pharmacological parameters of microemulsion 1 and microemulsion 2.

The results of the comparison in Table 6 above show that microemulsion 1 of the present invention is compatible with commercial propofol compositions of the same propofol concentration (1% w/v) ((R))) In contrast, on the parameters: the hypnotic and anesthetic latencies are shorter, the dosage to achieve the hypnotic and anesthetic effects is lower and the time required to recover from hypnosis and anesthesia is longer. Table 6 also shows that the resulting emulsion containing 1% (w/v) propofolThe pharmacological parameters are equivalent to those achievable with microemulsion 2 of the present invention, microemulsion 2 containing only half the propofol concentration (0.5% w/v) of the commercial emulsion.

These findings clearly demonstrate that the propofol microemulsions prepared according to the present invention, in an unexpected and unreported manner, have a greater hypnotic and anesthetic effect than commercially available or prior art propofol formulations.

Claims (8)

1. A transparent stable, ready-to-use, oil-in-water propofol microemulsion, comprising: propofol in the concentration range of 0.1% to 2% w/v, at a concentration range of 5% to 20% w/v, selected from the group consisting of those of the formula C₁₇H₃₅CO(OCH₂CH₂)_nOH or C₁₇H₃₅CO(OCH₂CH₂)_n·OCOC₁₇H₃₅Of polyethylene glycol stearate, glycerol for adjusting the osmotic pressure, sodium hydroxide for adjusting the final pH of the microemulsion in the range of 5.0 to 8.5, and the complementThe final composition is 100% w/v water for injection, with a particle size in the range of 1 to 100 nm.

2. The oil-in-water propofol microemulsion according to claim 1, wherein the propofol concentration ranges from 0.5% to 1% w/v.

3. The oil-in-water propofol microemulsion according to claim 1, wherein the surfactant is macrogol 15 hydroxystearate.

4. A transparent stable, ready-to-use, oil-in-water propofol microemulsion, comprising: propofol at a concentration of 0.5% or 1% w/v, macrogol 15hydroxystearate at a concentration of 10% w/v as a surfactant, glycerol at a concentration of 2.5% w/v as an osmolality adjusting agent, sufficient to provide sodium hydroxide at a concentration in the pH range 5.0 to 8.5, and water for injection to achieve 100% w/v of the final composition, having a particle size in the range 1-50 nm.

5. Use of the microemulsion according to claims 1 or 4 for the manufacture of a medicament for inducing and maintaining hypnosis, general anesthesia and/or sedation in humans.

6. Use of the microemulsion according to claims 1 or 4 for the manufacture of a medicament for inducing and maintaining hypnosis, general anesthesia and/or sedation in animals.

7. A process for the preparation of a transparent oil-in-water propofol microemulsion as claimed in claim 1, comprising the steps of:

(a) providing a first container containing a non-ionic polyethylene glycol stearate surfactant in an amount of 5 to 20% (w/v) of the final composition and maintaining the system under constant agitation and heating up to 50 ℃ until the surfactants fuse;

(b) adding water for injection in an amount of 5-10% of the total water for injection of the final composition and propofol in an amount of from 0.1 to 2% (w/v) to the mixture in the first vessel, and keeping the system under constant stirring;

(c) providing a second container with a stirring system, wherein the second container contains 50-85% of the total water consumption of the final composition;

(d) adding the mixture in the first container and glycerin into the second container, and continuously stirring until the mixture is homogenized;

(e) adding sodium hydroxide for adjusting the final pH of the microemulsion to a range of 5.0 to 8.5;

(f) supplementing water for injection until the volume of the final composition is reached, and continuously stirring until homogenization;

(g) the final composition was sterilized using a 0.22 μm filter.

8. The oil-in-water propofol microemulsion of claim 1, prepared by a process as claimed in claim 7.