HK1172272A - Pharmaceutical composition comprising propofol - Google Patents

Abstract

The invention provides novel pharmaceutical compositions comprising the active ingredient propofol. Preferably, propofol is dissolved in at least one semifluorinated alkane. The compositions, which are preferably liquid or gel-like, may optionally comprise further excipients. They may be used as fill material in capsules, as buccal or nasal sprays, or as aerosols for pulmonary administration. They are particularly useful for the transmucosal administration of propofol.

Description

Pharmaceutical compositions comprising propofol

Description of the invention

Background

Propofol (2, 6-diisopropylphenol, MW 178.27) is a pharmacologically active compound known as an effective intravenous anesthetic. It is commonly used to induce both anesthesia and anesthesia maintenance. It is characterized by its rapid onset (of action) and its relatively mild side effects.

Physically, propofol is a highly lipophilic compound that melts at about 19 ℃. At room temperature, it has the appearance of an oil. Its solubility in water or aqueous buffers is negligible, which makes propofol a highly challenging compound to prepare, inter alia, for intravenous administration, but also for other routes. The only ionizable group of the molecule is its hydroxyl group, which is however not suitable for forming water soluble salts due to its pKa of 11. At a pH of 6-8.5, the octanol/water partition coefficient of propofol is 6761: 1.

Propofol was first developed by the british pharmaceutical company ICI (now AstraZeneca) as a dissolved intravenous formulation containing a large amount of solubilizerA less tolerable excipient. Shortly after introduction into the market, several reports of allergic reactions have led to the formulation being brought out of the market. Several years later, AstraZeneca developed the trademark still in use today asThe novel propofol formulation of (a). The product was an o/w-emulsion containing 1% propofol and 10% soybean oil as the dispersed phase and 1.2% purified egg yolk lecithin as the emulsifier. The combined aqueous phase contained 2.25% glycerol and small amounts of EDTA and sodium hydroxide. In recent years, general emulsion formulations have also become available in many countries.

Propofol is used for general anesthesia, for the induction and maintenance of sedation in adults who inhale oxygen by mechanical means, and for surgical sedation. Other clinical uses that are also in the experimental phase include neuroprotection for the control of status epilepticus, the treatment of headaches, in particular migraine, the control of anxiety and acute brain injury. Such uses often require only a sub-hypnotic dose of propofol, as taught, for example, in WO00/54588A 1.

Propofol has a significant safety profile compared to other compounds used in anesthesia. The side effects are generally mild and easily controlled. The hypnotic effect of a single dose of propofol typically diminishes over a few minutes. Its rapid onset and recovery in combination with its amnestic effect has made this compound very useful for sedation and anesthesia. It did not appear to trigger emesis compared to similar drugs.

Typical side effects are a decrease in blood pressure and a temporary apnea with an induction dose. Mild myoclonic movements are usually observed. Another common problem with propofol emulsions is that they produce local pain at the site of injection or infusion, for which reason certain patients are pretreated with a local anesthetic such as lidocaine. It is believed that a small fraction of propofol dissolved in the aqueous phase of the emulsion contributes to this pain. Rare but more serious are dystonia, hyperlipidemia, pancreatitis and the so-called propofol infusion syndrome. This potentially fatal metabolic disorder has occurred in severely ill patients following long-term infusion of high doses of propofol in combination with catecholamines and/or corticosteroids.

More recently, other intravenous formulations of propofol have been clinically tested or introduced into the market. For example, a composition with only 5% soybean oil and 6% lecithin has been studied1% propofol emulsion. It is likely that the formulation may be associated with a lower risk of hyperlipidemia and pancreatitis. At the same time, it was found that the pain at the injection site was even more than usualMore clearly.

Other preparations such as propofol-Andpropofol relies on a higher proportion of Medium Chain Triglycerides (MCT) to replace Long Chain Triglycerides (LCT) in the oil component of the emulsion. It is speculated that both adult and pediatric patients tolerate MCT better than LCT. However, it may also release toxic compounds such as acetoacetate, β -hydroxybutyrate and octanoate.

For propofol, non-emulsion formulations have been proposed which comprise aqueous solutions in which the drug component is present in dissolved form with the aid of cyclodextrins. Cyclodextrins are water-soluble cyclic oligosaccharides capable of forming inclusion complexes with guest molecules. In particular, propofol solutions with hydroxypropyl- β -cyclodextrin and with sulfobutylether- β -cyclodextrin, respectively, have been investigated. However, it was not determined whether the pharmacokinetics of these formulations are comparable to propofol emulsions. However, high doses of cyclodextrins are often associated with haemolysis and nephrotoxicity.

US5,496,537 describes propofol aerosol formulations containing a hydrofluorocarbon propellant (propellant). However, propellant-propelled formulation inhalation is not easy for young and elderly patients who may not be able to perform the required respiratory movements. In addition, the pulmonary tolerance of propofol has not been determined.

Thus, further improvements in propofol formulations are needed. For example, there is a need for formulations that do not produce carrier-related toxic effects such as hyperlipidemia or hemolysis. In addition, there is a need for formulations and methods that allow propofol to be administered in a convenient, flexible, and painless manner.

Accordingly, it is an object of the present invention to provide propofol formulations that do not suffer from one or more of the disadvantages of the presently known formulations. Another object is to provide a method of administering propofol in a safe, tolerable and patient-friendly manner. Other objects will become apparent on the basis of the present description and patent claims.

Summary of The Invention

In a first aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of propofol and a semifluorinated alkane. The composition is typically a liquid formulation or a gel. In a preferred embodiment, propofol is dissolved in the semifluorinated alkane. The concentration of propofol in the composition may be 1wt. -% or higher, for example 5wt. -% or higher.

In a further aspect, the present invention provides the use of a semi-fluorinated alkane-based propofol composition. In particular embodiments, the composition is administered topically, for example to the oral or nasal mucosa, or topically by inhalation. Clinically, it can be used for induction or maintenance of sedation or anesthesia. Other therapeutic uses include preventing or treating headache pain, such as migraine, preventing or treating emesis, such as chemotherapy-induced emesis, controlling status epilepticus, anxiety, or providing neuroprotection in brain trauma.

In a further aspect, the invention provides pharmaceutical dosage forms, such as soft capsules, oral sprays, oral gels, oral liquids, nasal sprays, or inhalable aerosols in the form of metered dose aerosols or nebulizer solutions comprising such propofol compositions, and packages, containers, or kits comprising the same.

Still other aspects of the invention will be apparent from the detailed description below.

Detailed Description

According to a first aspect of the invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of propofol and a semifluorinated alkane.

As used herein, a pharmaceutical composition is a composition comprising at least one pharmacologically active ingredient or diagnostic agent in combination with at least one pharmaceutical excipient.

Propofol refers to the pharmacologically active compound 2, 6-bis (prop-2-yl) phenol (CAS number 2078-54-8), or any salt, solvate, complex, conjugate and derivative thereof. Preferably, the invention is practiced with the non-derivatized propofol in free form, as it is also present in currently available propofol drug products, for example

A pharmaceutically effective amount refers to a dose, concentration, or intensity that is useful for producing a desired pharmacological effect. The therapeutically effective amount of propofol can vary significantly depending on the patient (e.g., adult or young, healthy or diseased) and the type of effect desired (e.g., whether sedation, anesthesia, or headache management).

Semifluorinated alkanes are straight or branched alkanes in which some of the hydrogen atoms of the alkane have been replaced by fluorine. In a preferred embodiment, the semifluorinated alkanes (SFA) used in the present invention comprise at least one non-fluorinated hydrocarbon segment and at least one perfluorinated hydrocarbon segment. Particularly useful are compounds according to the formula F (CF)₂)_n(CH₂)_mH, SFA with one non-fluorinated hydrocarbon segment linked to one perfluorinated hydrocarbon segment, or according to the formula F (CF)₂)_n(CH₂)_m(CF₂)_oF, SFA with two perfluorinated hydrocarbon segments separated by one non-fluorinated hydrocarbon segment.

Another nomenclature used herein is to refer to the above-mentioned SFAs having two or three segments as RFRH and RFRHRF, respectively, where RF denotes a perfluorinated hydrocarbon segment and RH denotes a non-fluorinated segment. Alternatively, the compounds may be referred to as FnHm and FnHmFo, respectively, where F refers to the perfluorinated hydrocarbon segment, H represents the non-fluorinated segment, and n, m, and o are the number of carbon atoms of each segment. For example, F3H3 is used to represent perfluoropropylpropane. In addition, this type of nomenclature is commonly used for compounds having linear segments. Accordingly, unless otherwise indicated, F3H3 should be considered to refer to 1-perfluoropropylpropane, rather than 2-perfluoropropylpropane, 1-perfluoroisopropylpropane, or 2-perfluoroisopropylpropane.

Preferably, according to the formula F (CF)₂)_n(CH₂)_mH and F (CF)₂)_n(CH₂)_m(CF₂)_oThe semifluorinated alkanes of F have a fragment size ranging from 3 to 30 carbon atoms, i.e. n, m and o are independently selected from the range from 3 to 20. SFAs useful in the context of the present invention are also described in US6,262,126, EP-A965334, EP-A965329 and EP-A2110126, the disclosures of which are incorporated herein.

In other embodiments, the semifluorinated alkane is a compound according to formula RFRH, the fragments RF and RH of which are linear and each (but independently of each other) has from 3 to 20 carbon atoms. In another particular embodiment, the perfluorinated segment is linear and contains from 4 to 12 carbon atoms, and/or the non-fluorinated segment is linear and contains from 4 to 8 carbon atoms. Preferred SFAs include in particular the compounds F4H5, F4H6, F6H4, F6H6, F6H8 and F6H 10. The most preferred currently practiced invention are F4H5, F6H6, and F6H 8.

Optionally, the composition may comprise more than one SFA. For example, it may be useful to combine SFAs in order to achieve specific target properties, such as a particular density or viscosity. If mixtures of SFAs are used, it is further preferred that the mixture comprises at least one of F4H5, F4H6, F6H4, F6H6, F6H8 and F6H10, and in particular at least one of F4H5, F6H6 and F6H 8. In another embodiment, the mixture comprises at least two members selected from F4H5, F4H6, F6H4, F6H6, F6H8 and F6H10, and in particular at least two members selected from F4H5, F6H6 and F6H 8.

Liquid SFAs are chemically or physiologically inert, colorless and stable. Its typical density is from 1.1 to 1.7g/cm³And its surface tension can be as low as 19 mN/m. SFAs of RFRH type are water insoluble and slightly amphiphilic with enhanced lipophilicity associated with increased size of the non-fluorinated fragments.

Liquid SFAs of RFRH type are being used commercially in Ophthalmology, in particular for unrolling the retina for reapplication, for long-term tamponade of the eluate as a vitreous humor replacement (h.meiert et al, european journal of Ophthalmology, volume 10(3), pp 189-197, 2000) and as residual silicone oil after vitreo-retinal surgery. Experimentally, it has also been used as a blood substitute (H.Meiinert et al, Biomaterials, Art specialty Cells, and Immobilizaon Biotechnology, Vol. 21(5), pp. 583-95, 1993). These applications have identified SFAs as being physiologically well tolerated compounds.

On the other hand, SFA has not been used as an excipient in pharmaceutical products approved so far.

The inventors have now surprisingly found that SFAs are not only capable ofAn unexpectedly high amount of propofol dissolved; the resulting solution is also very advantageous in other respects. For example, it exhibits superior spreading behavior when applied to the skin or mucosa. At the same time, it does not produce any irritation normally observed when organic solvents are applied to the skin or mucous membranes. In addition, since SFA provides existing formulations such asWhich avoids the carrier-mediated hyperlipidemia problem.

The solubility of propofol in SFA was evident. For most SFAs including some of the most preferred members, i.e., F4H5, F6H6, and F6H8, propofol is freely miscible, which shows very high solubility in other SFAs. It has been found that SFA solutions having propofol concentrations as high as 960mg/mL are possible. Thus, the present invention also provides highly concentrated propofol liquid formulations. To enable safe and convenient dosing and administration, the compositions of the present invention should generally have a strength (i.e., propofol concentration) in the range of from about 0.001 to about 90 wt.%. In other embodiments, the propofol concentration is from about 0.01 to about 80wt. -%, or from about 0.1 to about 50wt. -%, or from about 1 to about 20wt. -%, or from about 2 to about 20wt. -%, respectively. In other embodiments, the strength is about 1wt. -% or higher, such as about 2wt. -%, 5wt. -%, 10wt. -%, 20wt. -% or 25wt. -%.

The combination of the high dissolution capacity of propofol, good spreading behavior and no irritation of e.g. mucous membranes also enables non-injectable administration of propofol for systemic efficacy. For example, the compositions of the present invention may be designed as concentrated solutions (e.g., 2 to 20wt. -%) for transmucosal (e.g., buccal or sublingual) administration. High drug concentrations in the composition provide a high driving force for absorption of the active ingredient into the blood stream through mucosal barriers. At the same time, the superior spreading behavior ensures intimate contact of the formulation with the mucosa. Since propofol is a small and lipophilic molecule, it is expected that in these cases it will be absorbed rapidly through the mucosa.

Alternatively, the composition may be administered by the conventional oral route, i.e. by ingestion. Optionally, liquid-filled hard or soft capsules may be used as a dosage form for this purpose. Simple oral solutions dispensed from suitable glass or plastic containers are also useful for more flexible dosing regimens.

For most purposes, it would be advantageous to take full advantage of the high solubility of SFA for propofol and design the composition to be completely solution, i.e., in which all or substantially all of the pharmaceutical ingredients contained therein are in dissolved form.

Preferably, the composition is in liquid form or gel form. As used herein, a gel is defined by its rheological properties. Gels useful as pharmaceutical dosage forms are semi-solid: it behaves like a solid when a low shear force is applied, and above a certain force threshold, the so-called "yield point", it behaves like a viscous fluid. Depending on the desired site and mode of application, it may be useful to design the compositions of the present invention as gels rather than as liquid solutions, for example, in order to achieve a longer residence time at the local site of application. On the other hand, the liquid form is particularly advantageous if the composition is used as a filling material for sublingual capsules, as a oromucosal spray or nasal spray or as an inhalable aerosol.

To convert the composition into a gel, a suitable gel-forming excipient or mixture of excipients may be added. These excipients may be solid materials such as solid SFAs that are miscible with the SFA or with the SFA in which the pharmaceutical ingredient is dissolved, or they may be materials that dissolve within the SFA like a colloid and form a three-dimensional network of related molecules that give rise to semi-solid behavior. Examples of excipients capable of gelling in anhydrous systems include colloidal silica (fumed silica) such as200, specific triterpenes (as taught for example in DE102004030044A 1), N-stearoyl-L-alanine methyl ester, sorbitan monostearate and lipophilic fibresCellulose derivatives such as ethyl cellulose.

Whether in liquid or gel form, the composition may contain other pharmaceutical excipients, if desired. For example, it may incorporate other organic solvents which are physiologically acceptable, such as ethanol, acetone, ethyl acetate, isopropanol, glycerol, propylene glycol, polyethylene glycol, liquid paraffin, triglyceride oils, hydrofluorocarbons such as HFA 134a and/or HFA 227, liquid mono-or diglycerides or similar solvents. Depending on the SFA that has been selected, the solvency of these solvents can be limited, which can limit the amount of solvent that can be incorporated. The presence of these solvents may be useful in order to alter the properties of the composition, such as density, viscosity, surface tension or vapor pressure. The presence of these solvents may also be useful in order to better dissolve another excipient still required in the composition, if the excipient does not readily dissolve in the selected SFA.

If it is desired to administer the composition in an aerosolized form, such as an intraoral aerosol, nasal aerosol or pulmonary aerosol, it may be useful to incorporate a propellant such as HFA 134a and/or HFA 227.

Depending on the particular use desired, it may or may not be desirable to add a hydrophilic organic solvent to also incorporate some small amount of water. In a preferred embodiment, the composition of the present invention is substantially free of water.

Optionally, the composition may comprise a surfactant. The incorporation of a surfactant may be useful in order to enhance the interaction of the formulation with aqueous liquids, for example with the mucus of the oral or nasal mucosa, and it may also improve spreading of the composition, particularly on moist body surfaces. Optionally, more than one surfactant may be used. Suitable surfactants may be selected from nonionic, anionic, cationic and zwitterionic surfactants that are physiologically acceptable for the desired route of administration. Examples of surfactants that may be useful include natural and purified lecithin, hemi-saltsSynthetic phospholipids, poloxamers, polyglycolized glycerides,d-alpha-tocopheryl polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80,Sorbitan monooleate, a,M-1944CS、M-2125CS、44/14、767 and PEG 300, 400 or 1750.

Additionally, the composition may include an antioxidant, optionally in combination with a synergist, for example if one of the excipients in the formulation is susceptible to oxidative degradation. Examples of potentially suitable antioxidants and synergists include vitamin E or vitamin E derivatives such as vitamin E-TPGS, lycopene and its derivatives, gallic acid esters, butyl hydroxyanisole and butylated hydroxytoluene.

Other pharmaceutical excipients that may be added as desired include coloring agents, flavoring agents, taste-masking agents, sweetening agents, bioadhesives, viscosity modifiers, stabilizers, preservatives and the like. Examples of suitable fat-soluble flavoring agents include essential oils such as peppermint and eucalyptus, camphor and menthol. Examples of useful preservatives include sorbic acid, methyl paraben, ethyl paraben, propyl paraben, butyl paraben and benzyl paraben, benzoic acid, benzyl alcohol, chlorobutanol, phenol, phenoxyethanol, chlorocresol and m-cresol. However, in a preferred embodiment, the composition is substantially free of lipids such as triglycerides or phospholipids to avoid lipid-related toxicities such as hyperlipidemia.

On the other hand, and in contrast to currently known propofol formulations, since the compositions of the present invention are preferably anhydrous formulations, they will generally not require the incorporation of preservatives. Accordingly, other embodiments of the present invention are anhydrous, preservative-free compositions comprising propofol and at least one SFA. Since preservatives are often associated with the hazards of deleterious reactions such as allergies, it is a considerable advantage of the present invention to be able to provide preservative-free compositions that are not susceptible to contamination by microorganisms.

In other embodiments, the compositions of the present invention are sterile. After filling it into suitable primary packaging means, sterility can be achieved by sterilizing the formulation, for example by autoclaving or gamma-sterilization. Alternatively, the composition may be sterile filtered and then aseptically filled into sterile primary packages such as glass or plastic vials and sealed.

In yet another aspect, the invention also relates to a dosage form comprising the composition described herein. Dosage form is understood to be the type of pharmaceutical composition or pharmaceutical product suitable for administration. For example, contemplated dosage forms that may contain the composition are soft gelatin capsules, (oral) oral sprays, (oral) oral liquids, (oral) oral gels, nasal sprays, metered dose aerosols, nebulizer solutions, ear drops, rectal enemas, and the like.

Preferred types of soft gelatin capsules are designed for oral or intraoral administration. Like most conventional capsule formulations, it can simply be swallowed. For oral administration, the capsule shell can be modified to readily chew and break to release the liquid or gel-like composition into the oral cavity. Due to the nature of propofol and its high concentration in the composition, the drug can thus be absorbed into the bloodstream through the oral mucosa, e.g. sublingual, gingival or buccal mucosa. A particular advantage of soft gelatin capsules with a liquid or semisolid fill for oral administration is that they combine the typical advantages of solid dosage forms (accurate dosage, convenient handling and administration, high stability and long shelf life) with the absorptive capacity of the oral mucosa, which leads to a rapid onset of pharmacological effects without any possibility of bioavailability-limiting first-pass effects.

Alternatively, if the composition is administered in other oral dosage forms, such as an oral liquid or spray, these embodiments have the advantage that the application of a flexible dosing regimen is particularly easy. For example, the dosage can be readily adjusted to take into account the desired pharmacological effect (e.g., whether sedation, anesthesia, or migraine control), the type of patient (diseased or healthy, adult, or young). In addition, the administration of an oral liquid or spray for oromucosal absorption allows for dose-to-effect type (dosing-to-effect) treatments, wherein successive doses are administered until the desired therapeutic effect is observed on the patient.

In other embodiments, the composition is for nasal administration. Depending on the use, the composition may be provided as a nasal spray or in the form of an aerosolized aerosol, with the aerosol droplet size distribution and fluid dynamics adjusted to achieve high aerosol deposition on the nasal mucosa. Absorption of small lipophilic molecules into the bloodstream through the nasal mucosa is possible and since the compositions of the present invention contain high concentrations of pharmaceutical ingredients, and are in well-tolerated carriers, they are well-suited to achieving this route of administration. In addition, it has been found that the compositions of the present invention can be readily atomized using conventional nasal spray bottles with nozzles, producing droplets of about 0.1 to 10 μm in diameter.

Indeed, there are other advantages according to embodiments in which the composition is packaged and provided in a spray bottle with a nozzle: it is useful for both intraoral and nasal administration.

As mentioned, the composition may also be administered into the lungs by inhalation using, for example, a metered dose inhaler or nebulizer. This is possible because even when inhaled, SFAs are highly biocompatible and physiologically inert.

Preferably, the compositions and dosage forms provided by the present invention are useful as medicaments for all patients who may benefit from receiving propofol. In particular, it is particularly advantageous to propose medical uses for inducing or maintaining anaesthesia or sedation, preventing or treating headaches such as migraine, treating or preventing emesis such as chemotherapy-induced emesis, central nervous tissue protection (neuroprotection) in brain trauma or injury, and controlling anxiety.

In addition, the compositions and dosage forms are also useful as veterinary agents for both livestock and pets. In particular, the use in inducing and/or maintaining anesthesia and sedation and controlling anxiety is recommended.

The following examples serve to illustrate the invention; however, these examples should not be construed as limiting the scope of the invention.

Examples

Example 1

Under sterile conditions, to 100mL of perfluorobutylpentane (F4H5) was added 1mg (5.6X 10) with stirring^-3mmol) of propofol to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 2

Under aseptic conditions, 1mg (5.6 x 10) of perfluorobutylpentane (F4H5) was added to 1mL with stirring^-3mmol) of propofol to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 3

Under sterile conditions, 100mg (0.56mmol) of propofol was added to 1mL of perfluorobutylpentane (F4H5) with stirring to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 4

Under sterile conditions, 1g (5.6mmol) of propofol was added to 1mL of perfluorobutylpentane (F4H5) with stirring to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 5

Under sterile conditions, 100mg (0.56mmol) of propofol was added to 1mL of perfluorohexyloctane (F6H8) with stirring to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 6

Under sterile conditions, 100mg (0.56mmol) of propofol was added to 0.5mL of perfluorohexyloctane (F6H8) and 0.5mL of perfluorobutylpentane (F4H5) with stirring to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 7

Under sterile conditions, 1g (5.6mmol) of propofol was added to 1mL of perfluorohexyloctane (F6H8) with stirring to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 8

To 1mL of perfluorobutylpentane (F4H5) under sterile conditions, 100mg (0.56mmol) of propofol and 2mg (4.6X 10) were added with stirring^-3mmol) of alpha-tocopherol to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 9

To 1mL of perfluorohexyloctane (F6H8), 100mg (0.56mmol) of propofol and 30mg (7 mmol) of propofol were added under sterile conditions with stirring*10^-2mmol) of alpha-tocopherol to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 10

To 1mL of perfluorobutylpentane (F4H5) under sterile conditions, 100mg (0.56mmol) of propofol and 10mg (6.6X 10) were added with stirring^-2mmol) of camphor to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 11

Under sterile conditions, 100mg (0.56mmol) of propofol and 100mg (2.2mmol) of ethanol are added to 1mL of perfluorobutylpentane (F4H5) with stirring to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 12

Under sterile conditions, 100mg (0.56mmol) of propofol and 100mg (2.2mmol) of ethanol were added to 1mL of perfluorohexylhexane (F6H6) with stirring to form a clear solution. After stirring for a further 15 minutes, the solution was sterile filtered and filled into sterile brown glass vials which were then sealed.

Example 13

Two propofol solutions were prepared having a nominal propofol content of 400mg/g, similar to example 1. As solvent, the first part of the solution comprises perfluorobutylpentane (F4H5), while the second part of the solution comprises perfluorohexyloctane (F6H 8). No other ingredients were used. To test their stability, sample vials of each solution were stored at 25 ℃/60% RH, 30 ℃/65% RH and 40 ℃/75% RH, respectively. After one month of storage and three months of storage, the samples were analyzed by GC/MS according to ph.eur.2.2.2. As a result, the propofol content in all samples was well above 95% of the nominal value, and also well above 95% of the actual content measured immediately after the solution was prepared, indicating good stability of the formulation. Table 1 shows the results in detail. The percentages indicated are relative to the nominal propofol content.

TABLE 1

Example 14

Similar to example 13, two propofol solutions having a nominal propofol content of 300mg/g were alternatively prepared using perfluorobutylpentane (F4H5) or perfluorohexyloctane (F6H8) as the sole solvent. Three anesthetized Wistar rats were orally administered an amount of 100mg propofol per Kg body weight of each formulation. Specifically, Wistar rats weighing 348 ± 24g were randomly divided into experimental groups (n ═ 3 for each group). Animals were pre-oxygenated with ketamine (a)10%, Pfizer, Karlsruhe, Germany) and xylazine (Bayer vital, levirkusen, Germany). Vascular catheters (Portex, Smiths medical, Kent, UK) were placed in the femoral artery and vein. The anesthetized animal was placed in a supine position, the neck was dissected open and a tracheotomy was performed. To avoid displacement of the stomach or intestine of the test compound, the adjacent esophagus was then ligated. Arterial blood pressure was monitored by connecting the vascular catheter to a standard pressure transducer. Heart rate was monitored by Electrocardiogram (ECG). The body temperature was continuously monitored using a rectal probe and maintained normal using an electric heating pad. Anesthesia was maintained with continuous intravenous infusion of ketamine and xylazine until completion of the experiment. Arterial pressure and ECG were monitored and acquired by a calibrated specific multichannel online recorder (MedIS, Medical Device Integration System, hochschulem and heim, Germany). By FabianNeonatal ventilator (Acutronic Medical Systems AG, Hirzel, Switzerland) in pressure control mode (IPPV), and FiO₂0.5, tidal volume of 6ml/kg, and positive end respiratory pressure of 3cm H₂O and the respiration rate is 70-80min^-1The animals were ventilated.

A baseline blood sample (0.2 μ l) was collected prior to placing the test compound (baseline value) in the mouth. Propofol formulations based on F4H5 and F6H8 were administered as large pills into the buccal pouch of the animal using a laboratory pipette. Each animal received 100mg/kg body weight of each solution. On average, each animal received 34. + -.2 mg of propofol. Blood samples (0.2 μ l) were collected at 5, 10, 15, 30, 60, 90 and 120 minutes after oral administration of the test compound. The samples were centrifuged and stored at-20 ℃ until analysis. Determination of propofol concentration was performed by Mass Spectrometry (MS) and High Performance Liquid Chromatography (HPLC).

As a result, hemodynamic monitoring provides evidence that the formulation is well tolerated. No changes in heart rate and arterial blood pressure were observed.

In the case of the F4H 5-based formulation, systemic absorption of propofol was indicated by an increase in mean plasma levels above 100ng/ml after 10 minutes and in the case of the F6H 8-based formulation after 15 minutes. Within the sampling time, after 120 minutes, a maximum plasma level of 334ng/ml was observed based on the F4H5 formulation, and after 60 minutes 259ng/ml in the case of the F6H8 based formulation. However, at least for the F4H 5-based formulation, the actual maximum plasma level was not yet reached as shown at the end of the experiment. The concentrations at all sampling times are provided in table 2. Generally, for example, in a particular care setting, the propofol concentrations are slightly lower than those typically observed in conventional anesthesia with propofol, and, despite this, are considered effective for sedation.

TABLE 2

C_av: average propofol plasma concentration (n ═ 3)

SD: standard deviation of

Claims (15)

1. A pharmaceutical composition comprising a therapeutically effective amount of propofol and a semifluorinated alkane.

2. The composition of claim 1, wherein the semifluorinated alkane is of formula (la)

RFRH

Or formula

RFRHRF

The compound of (a) to (b),

wherein RF is a perfluorinated hydrocarbon segment with 20 or less carbon atoms, and

wherein RH is a non-fluorinated hydrocarbon fragment with 3 to 20 carbon atoms.

3. The composition of claim 2, wherein the semifluorinated alkane is of formula (la)

RFRH

The compound of (a) to (b),

wherein RF is a linear perfluorinated hydrocarbon segment with 3 to 10 carbon atoms, and

wherein RH is a linear alkyl group having 3 to 10 carbon atoms.

4. The composition of claim 3, wherein the semifluorinated alkane is selected from the group consisting of F4H5, F6H6, and F6H 8.

5. The composition of any preceding claim, wherein the concentration of propofol is about 1wt. -% or more.

6. A composition according to any preceding claim, wherein substantially all propofol comprised in the composition is in dissolved form.

7. A composition according to any preceding claim, which is in the form of a liquid or gel.

8. A composition according to any preceding claim which is substantially free of lipids, such as triglycerides or phospholipids.

9. A pharmaceutical dosage form comprising the composition of any preceding claim.

10. The dosage form of claim 9, selected from the group consisting of a soft capsule or oral spray, a nasal spray, an inhalable aerosol, an oral gel, and an oral liquid.

11. A pharmaceutical kit comprising a container and the composition of claims 1-8 therein, wherein the container comprises a means for aerosolizing the composition.

12. Use of the composition of claims 1 to 8 or the dosage form of claims 9 or 10 as a medicament.

13. The use of claim 12, wherein the medicament is for oral, oromucosal or nasal administration.

14. The use according to claim 12 or 13, wherein the medicament is for inducing anaesthesia, sedation, for neuroprotection in brain injury, or for the treatment of migraine or emesis.

15. Use of the composition of claims 1 to 8 or the dosage form of claims 9 or 10 as a veterinary medicament.