WO1996032135A1 - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- WO1996032135A1 WO1996032135A1 PCT/GB1996/000737 GB9600737W WO9632135A1 WO 1996032135 A1 WO1996032135 A1 WO 1996032135A1 GB 9600737 W GB9600737 W GB 9600737W WO 9632135 A1 WO9632135 A1 WO 9632135A1
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- beta
- cyclodextrin
- hydroxypropyl
- propofol
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
Abstract
A pharmaceutical composition for administration as an injection or as a retention enema contains an inclusion complex of propofol and 2-hydroxypropyl-beta-cyclodextrin, with approximately a 1:2 mol/mol stoichiometry the composition including a co-solvent where necessary. The pharmaceutical composition is prepared by dissolving in water an amount of 2-hydroxypropyl-beta-cyclodextrin and then adding, with mixing, an amount of propofol to provide the desired molar ratio, and if necessary, adding the pharmaceutically acceptable co-solvent.
Description
PHARMACEUTICAL COMPOSITION
BACKGROUND OF THE INVENTION
This invention relates to methods of preparing a pharmaceutical composition for administration as an injection or as a retention enema comprising an inclusion complex of propofol and 2-hydroxypropyl-beta-cyclodextrin. Compositions according to the invention are stable non-colloidal aqueous solutions containing up to 30 mg/ml propofol convenient and suitable for direct intravenous administration, or use as a retention enema.
Propofol (2,6 di-isopropylphenol) is widely used as an induction agent for anaesthesia. The high lipophilicity of the agent facilitates rapid penetration of the drug into the central nervous system thus providing rapid onset of action. Owing to the strong lipophilic nature of propofol, the commercial
intravenous preparation is formulated as a lipid emulsion in soya bean oil. egg phospholipids and glycerol. Formation of the emulsion demands sophisticated industrial processes to ensure nanoparticulate dimensions of the lipid phase to enable sterilization by filtration and maintain stability.
Significant pain on injection has been associated with the emulsion formulation. [Propofol , the newest induction agent of anaesthesia; Kanto, J. H. Int. J. Clin. Pharmacol. Ther. Toxicol. 1988, 26 (1) 41-57]. Propofol is currently available commercially as 20 milliliter ampoules containing 10 mg/ml propofol. Propofol is given by intravenous injection for the induction of anaesthesia by administering 40 mg every 10 seconds. Most adults will be anaesthetized by a dose of 2,0 to 2,5 mg per kg body-weight [Martindale 29, 1125]. The same propofol formulation has also been used as a retention enema for pre-operative paediatric sedation, where the contents of the ampoule are introduced rectally. The commercially available emulsion does not however have acceptable retention characteristics.
There is a need for safe and effective intravenous formulations of propofol which are industrially simple to produce and which may cause less pain on injection, and which may also be used as retention enemas.
Cyclodextrins are cyclic oligosaccharides with a cone-like shape. The interior of the cone behaves as a hydrophobic cavity whilst the exterior of the cone is hydrophilic. The former property enables cyclodextrins to form inclusion complexes with a wide variety of lipophilic molecules which "fit" into the cavity while the latter property facilitates aqueous solubility. Cyclodextrin derivatives such as 2-hydroxypropylated beta-cyclodextrins have been extensively studied for use as parenteral drug carriers owing to their high water solubility and low toxicity [Cyclodextrins in Pharmacy. Frδmming, K-
H. & Szejtli, J. 1994 Kluwer Academic Publishers pp 1-44]. A particularly useful grade of 2-hydroxypropyl-beta-cyclodextrin is produced when the degree of 2-hydroxypropylation is controlled to between 3,9 and 5,1 2- hydroxypropyl substituents per beta-cyclodextrin molecule [ZA Pat. No. 84/10042 to Janssen Pharmaceutica] commercially available as Encapsin- HPB™. Clinical studies on 8 healthy volunteers showed that intravenous infusion of Encapsin-HPB at a dose of 3 g, given as a single dose, was safe and well tolerated [Junge, W. and Seiler, K.-U. Janssen Clinical Research Report July 1988].
The following prior art is known in relation to cyclodextrins and propofol.
PCT International patent application WO 931771 1 to Australian Commercial Research and Development Limited, Australia teaches the preparation of 6A- amino-6A-N-(4-aminobutyl)-6A-deoxy-beta-cyclodextrin derivatives and formulation of inclusion complexes of propofol or alfaxolone with the modified cyclodextrins.
The preparation and central action of propofol/hydroxypropyl-beta- cyclodextrin complexes in rabbits has been reported [Viernstein, H., Stumpf Ch., Spiegl, P. and Reiter, S. Arzneim. -Forsch. 1993, 43, 818-823]. Solid inclusion complexes of propofol/2-hydroxypropyl-beta-cycIodextrin were prepared by dissolving the propofol in ethanol to obtain concentrations between 10 and 20 %. One part of the drug solution was added to up to three parts of 2-hydroxypropyl-beta-cyclodextrin and kneaded in a mortar until the solvent evaporated. The resulting powder was dried under vacuum to constant weight. Proof of inclusion complexation in the solid state was provided by infrared spectroscopic analysis and differential scanning calorimetry. From phase solubility studies in phosphate buffer the stability
constant of the propofol/ 2-hydroxypropyl-beta-cyclodextrin complex with 1 : 1 mol/mol stoichiometry was estimated to be 2940 M"'. The solid complexes were dissolved in artificial plasma, leading to a colloidal solution which was suitable for intravenous administration. Compared with commercial propofol injection no differences were observed between the two dosage forms in the onset, duration and maximal effect.
In a study to determine smooth muscle relaxant effects of propofol and ketamine in isolated guinea pig trachea, propofol was prepared as a 0,1M aqueous solution in 40% w/v 2-hydroxypropyl-beta-cyclodextrin (corresponding to 17,83mg/ml propofol in 400mg/ml 2-hydroxypropyl-beta- cyclodextrin or a mass ratio of 1 :22,4 or a molar ratio of 1 :2,8 mol mol propofol to 2-hydroxypropyl-beta-cyclodextrin) and as the commercial lipid emulsion [Pedersen, CM., Thirstup, S. and Nielsen-Kudsk, J.E. Eur. J. Pharmacol. 1993, 238, 75-80]. Propofol showed three times higher muscle relaxant activity when solubilized with 2-hydroxypropyl-beta-cyclodextrin compared with the lipid emulsion.
SUMMARY OF THE INVENTION
According to a first aspect of the invention there is provided a method of preparing a pharmaceutical composition for administration as an injection or as a retention enema comprising an inclusion complex of propofol and 2- hydroxypropyl-beta-cyclodextrin with approximately a 1:2 mol/mol stoichiometry, which method includes the steps of: (a) dissolving in water an amount of 2-hydroxypropyl-beta-cyclodextrin and then adding, with mixing, an amount of propofol to provide an approximate molar ratio of propofol to 2-hydroxypropyl-beta-
cyclodextrin of 1 :2 to 1 :2,5, to produce a clear colourless solution; and (b) if necessary adjusting the osmolality of the solution by adding a pharmaceutically acceptable osmolality adjustment agent.
The solution contains the inclusion complex of propofol and 2- hydroxypropyl-beta-cyclodextrin with approximately a 1 :2 mol/mol stoichometry and is suitable for use as an injection or as a retention enema, to induce sedation or anaesthesia. The excess of 2-hydroxypropyl-beta- cyclodextrin present in the solution acts to stabilize the complex.
According to a second aspect of the invention there is provided a method of preparing a pharmaceutical composition for administration as an injection or as a retention enema comprising an inclusion complex of propofol and 2- hydroxypropyl-beta-cyclodextrin with a stoichiometry of approximately 1 :2 mol/mol, which method includes the steps of:
( 1 ) dissolving in water an amount of 2-hydroxypropyl-beta-cyclodextrin and then adding, with mixing, an amount of propofol to provide an approximate molar ratio of propofol to 2-hydroxypropyl-beta- cyclodextrin of between 1:1,5 and 1 :<2, and then adding a pharmaceutically acceptable co-solvent, to produce a clear colourless solution.
Again, the solution contains the inclusion complex of propofol and 2- hydroxypropyl-beta-cyclodextrin with approximately a 1:2 mol mol stoichiometry and is suitable for use as an injection or as a retention enema, to induce sedation or anaesthesia. The excess of propofol present which is not complexed is solubilized by the co-solvent, to give a clear colourless solution.
According to a third aspect of the invention there is provided a pharmaceutical composition produced by either of the two methods described above.
The two methods of the invention may include the additional steps of:
(i) addition to the solution of a pharmaceutically acceptable anti-oxidant such as acetylcysteine and/or EDTA, or sodium metabisulphite, or potassium nitrate and/or a preservative such as benzalkonium chloride or bronopol or chlorhexidine gluconate or chlorobutanol;
(ii) degassing the solution with nitrogen;
(iii) sterilising the solution by filtration; and
(iv) filling the solution into an ampoule.
In the first method of the invention the molar ratio of propofol to 2- hydroxypropyl-beta-cyclodextrin used is approximately 1 :2 to 1 :2,5 mol/mol, such that the bolus dose of a composition containing 200 mg propofol contains about 3,1 to 4,3g 2-hydroxypropyl-beta-cyclodextrin.
In the second method of the invention there is used a pharmaceutically acceptable co-solvent so that the molar ratio of propofol to 2-hydroxypropyl- beta-cyclodextrin may be reduced to between 1:1,5 and 1 :<2 such that the bolus dose of a composition containing 200 mg propofol may contain below 3,0g 2-hydroxypropyl-beta-cyclodextrin.
In step (a) of the first method and step (1) of the second method, the temperature at which dissolution takes place may be between ambient temperature and an elevated temperature up to about 50°C.
In step (a) of the first method and in step (1) of the second method of the
invention, the propofol is preferably introduced in a controlled manner over a period of time with vigorous mixing, to the solution containing the calculated amount of 2-hydroxypropyl-beta-cyclodextrin.
The average degree of substitution of the 2-hydroxypropyl-beta-cyclodextrin used is preferably between 2,5 and 9,0, and more preferably between 3,9 and 5,1 2-hydroxypropyl groups per beta-cyclodextrin molecule.
In step (b) of the first method of the invention, the pharmaceutically acceptable osmolality adjustment agent may be selected from glycerol, dextrose, mannitol and sorbitol. In this step, there may also be a final volume adjustment.
In step (1) of the second method of the invention, the pharmaceutically acceptable co-solvent may be selected from glycerol, a glycol such as propylene glycol or preferably polyethylene glycol with an average molecular mass of 300, a macrogol, or a water soluble polymeric organic compound such as polyvinyl pyrrolidone or a hydroxyalkylated starch derivative such as hydroxyethylated starch with an average molecular mass of 200 000.
The pharmaceutical composition of the invention preferably has a concentration of propofol of 5 mg per millilitre or more preferably about 10 or 20 mg per millilitre.
The composition may be formulated in unit dose form, each unit dose containing from 50 to 400 mg inclusive of propofol. The preferred unit dose contains 200 mg propofol.
The unit dose may be further diluted if required with suitable diluents such as water for injection or dextrose.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the structures and proton notations for propofol and 2- hydroxypropyl-beta-cyclodextrin. The propofol structure (top) shows equivalent protons with prime notation. The 2-hydroxypropyl-beta- cyclodextrin structure (bottom) is composed of seven glucopyranose units shown with the 2-hydroxypropyl (CH3CH(OH)CH2-) groups omitted which may be substituted on the 2', 3' or 6' hydroxyl oxygens;
Figure 2 shows the assigned 500 MHz proton magnetic resonance spectrum of a solution containing propofoL/2-hydroxypropyl-beta-cyclodextrin in a 1:2 mol/mol stoichiometry in deuterated water recorded on a Bruker AMX-500 nuclear magnetic resonance spectrometer;
Figure 3 shows the assigned two-dimensional nuclear Overhauser enhancement spectrum of the propofol 2-hydroxypropyl-beta-cyclodextrin 1 :2 mol/mol complex in deuterated water recorded in the rotating frame on a Bruker AMX-500 nuclear magnetic resonance spectrometer;
Figure 4a shows a proton magnetic resonance based molecular model of the aqueous inclusion complex formed between propofol and 2-hydroxypropyl- beta-cyclodextrin, with a perspective view being shown and with the propofol being shown in bold and the 2-hydroxypropyl groups omitted;
Figure 4b shows a space filling model of the complex obtained in Figure 4a
indicating the complete molecular encapsulation of propofol by two cyclodextrin molecules; and
Figure 4c shows the model obtained in Figure 4b with the Z-axis being partially cut away to reveal the interaction between the isopropyl groups of propofol and the hydrophobic cyclodextrin cavity according to the NMR results shown in Figure 3.
DESCRIPTION OF EMBODIMENTS
This invention relates to two methods of preparing a pharmaceutical composition for administration as an injection or as a retention enema comprising an inclusion complex of propofol and 2-hydroxypropyl-beta- cyclodextrin. Compositions according to the invention are stable non- colloidal aqueous solutions containing up to 30 mg/ml propofol convenient and suitable for direct intravenous administration. The first method of the invention is preferred.
The major step of both methods of the invention is gradually to add the propofol to a concentrated solution of a calculated amount of 2- hydroxypropyl-beta-cyclodextrin in purified water with vigourous mixing at a temperature from ambient temperature but preferably between 30 and 50 °C. The solution is allowed to cool to room temperature with continued stirring.
In the first method of the invention when no co-solvent is used, the propofol and the 2-hydroxypropyl-beta-cyclodextrin are used in an approximate molar ratio of 1 :2 to 1 :2,5 to produce a complex with approximately a 1:2 mol/mol
stoichiometry.
In the second method of the invention when a co-solvent is used, the propofol and the 2-hydroxypropyl-beta-cyclodextrin are used in an approximate molar ratio of 1 :1,5 to 1 :<2 to again produce a complex with a stoichiometry of approximately 1:2 mol/mol.
Beta-cyclodextrin consists of 7 glucose units in a ring structure, also referred to as cyclohepta-amylose. Each glucose unit contains 3 hydroxyl groups which may be etherified by 2-hydroxypropylation to give 2-hydroxypropyl- beta-cyclodextrin (HPB). HPB is produced by reacting beta-cyclodextrin with propylene oxide under controlled conditions so that the average molar substitution (mole propylene oxide per glucose unit) is between 0,25 and 1. This implies that only between 1,75 and 7 hydroxypropyl groups are introduced per beta-cyclodextrin molecule, out of a theoretically possible 21. The average degree of substitution (D.S.) per beta-cyclodextrin molecule may be calculated from the 'H-NMR integrals corresponding to the anomeric and methyl signals between 4,95-5,3 and 0,9-1,2 ppm respectively from the NMR spectrum of HPB in D2O. The approximate molecular mass may in turn be calculated from the value of D.S.
(1) Calculation of the degree of substitution (D.S.) D.S. = 7b ÷ 3a
wherein a is the integral of anomeric protons and b is the integral of methyl protons.
(2) Calculation of molecular mass (M.M.)
M.M. = (1135 - D.S.) ÷ (59 x D.S.).
Using this method of calculation, and using 2-hydroxypropyl-beta- cyclodextrin with an average degree of substitution of 4,6, the following mol/mol and mass/mass figures are obtained:
Propofol-HPB mol/mol P r o p o f o l : H P B mass/mass
1:1,5 1:11,79
1 :2 1 : 15,72
1 :2,5 1 :19,65
The average degree of substitution of the 2-hydroxypropyl-beta-cyclodextrin is preferably between 2,5 and 9,0 and more preferably between 3,9 and 5,1 2-hydroxypropyl groups per beta-cyclodextrin molecule. 2-hydroxypropyl- beta-cyclodextrin with an average degree of substitution of 4.6 has a corresponding average molecular mass of around 1400 grams per mole as determined by nuclear magnetic resonance spectrometry. The mass ratio of propofol to 2-hydroxypropyl-beta-cyclodextrin may be between 1 :11,0 to 1 :20,0 or more preferably between 1 :15,72 to 1 :19,65, when the average degree of substitution is 4,6 2-hydroxypropyl groups per cyclodextrin molecule.
In the second method of the invention a pharmaceutically acceptable co- solvent or mixture of co-solvents is added to the solution. The co-solvents may be selected from the group consisting of glycerol, glycols, macrogols or suitable water soluble polymeric organic compounds such as polyvinyl pyrrolidone or hydroxyalkylated starch derivatives. Glycerol may be used in the concentration range of 3 to 10 % m/v (mass volume) of the final solution
volume. The glycol is preferably propylene glycol or more preferably polyethylene glycol with an average molecular mass of 300 used in the concentration range of 1 to 10 % m/v of the final solution volume. The hydroxyalkylated starch is preferably hydroxyethylated starch with an average molecular mass of 200 000.
In the absence of co-solvent it may be desirable to modify or adjust the osmolality of the solution by addition of suitable organic osmolality adjustment agents such as glycerol, dextrose, mannitol or sorbitol.
The solution may contain other physiologically compatible compounds such as an anti-oxidant, for example acetylcysteine and/or EDTA, or sodium metabisulphite or potassium nitrate, and/or a preservative, for example benzalkonium chloride or bronopol or chlorhexidine gluconate or chlorobutanol.
The solution is brought to final volume and is degassed with nitrogen. The solution is sterilized by filtration and aseptically transferred into vials or ampoules optionally under a nitrogen atmosphere.
The composition of the invention preferably has a concentration of propofol of 5 mg per millilitre, more preferably about 10 or. 20 mg per milliter up to 30 mg per millilitre.
The composition may be formulated in unit dose form, each unit dose containing from 50 to 400 mg inclusive of propofol. The preferred unit dose contains 200 mg propofol.
The composition produced by the methods of the invention may be used for
the induction and short term maintenance of anaesthesia by intravenous injection.
The composition is suitable for further dilution if required in conventional intravenous diluents such as water for injection or dextrose solution.
The composition is suitable for Y-site administration in suitable solutions such as dextrose solution.
The composition is also suitable for use as a retention enema, particularly for pre-operative paediatric sedation. The aqueous nature of the composition has advantages over the conventional emulsion-based formula, as aqueous formulations are generally better retained than oily formulations.
It is to be noted, that as stated above, the reference to Pedersen, CM., Thirstup, S. and Nielsen-Kudsk, J.E. Eur. J. Pharmacol. 1993, 238, 75-80, teaches that a 17,83 mg/ml solution of propofol is prepared using 400 mg hydroxypropyl-beta-cyclodextrin per ml of solution. This corresponds to a propofol/hydroxypropyl-beta-cyclodextrin mol/mol stoichiometry of 1 :2,8 and a lowest mass/mass ratio, irrespective of the degree of substitution of 1 :22,43. It has been found that the stability of propofol-hydroxypropyl-beta- cyclodextrin solutions, in the absence of co-solvents, increases with increasing hydroxypropyl-beta-cyclodextrin concentration. However, the amount of hydroxypropyl-beta-cyclodextrin which may be used intravenously is limited by toxicological considerations. This is of special concern in the case of propofol-hydroxypropyl-beta-cyclodextrin complexes since the product may be given continuously by intravenous infusion for maintenance anaesthesia. It has been found that the optimum hydroxypropyl-beta- cyclodextrin concentration to provide a stable aqueous solution containing
propofol in a clinically useful concentration of 10 mg/ml, which may be infused to maintain anaesthesia for at least one hour, without undue hydroxypropyl-beta-cyclodextrin toxicological hazard, is a maximum of about 215 mg hydroxypropyl-beta-cyclodextrin per ml of solution, corresponding to a propofol/hydroxypropyl-beta-cyclodextrin mol/mol stoichiometry of 1 :2,5. when the average degree of substitution of 2- hydroxypropyl-beta-cyclodextrin is 4,6.
The following examples relate to the preparation of inclusion complexes between propofol and 2-hydroxypropyl-beta-cyclodextrin. their characterization and pharmaceutical compositions containing them.
Example 1
To a 5 ml glass beaker 0,316 g 2-hydroxypropyl-beta-cyclodextrin D.S. 4,6 (Janssen Biotech) is added. 2,0 ml of 99,8 % deuterated water (Merck) is added and the solution is stirred with a magnetic stirrer until dissolution is complete. The solution is warmed to 45 °C Pure propofol (Ethyl Corporation) is drawn up into a syringe and 0,02 g is gradually introduced into the solution with vigourous stirring over 5 minutes. Once all the propofol is added the heat is removed and the solution is stirred until ambient temperature is reached. The solution is filtered through a 0,22 micron filter and 1,0 ml is transferred to a 5 mm nuclear magnetic resonance (NMR) tube. The remainder of the solution is analyzed by high performance liquid chromatography (HPLC) for propofol content. The amount of propofol is found to be 10,0 ± 0,1 mg per millilitre.
The NMR sample is placed in the probe of a Bruker AMX-500 NMR spectrometer operating at 500 MHz with probe temperature at 303 K. A one dimensional proton spectrum of the sample is recorded with 128 scans. The
spectral assignments were made on the basis of reported values for cyclodextrins and substituted phenols and on the basis of chemical shift, signal intensity, multiplicity of signals and proton correlations obtained from the two-dimensional spectra. The assigned proton spectrum is shown in Figure 2 with the proton notations shown in Figure 1.
The nature of the inclusion complex formed between propofol and 2- hydroxypropyl-beta-cyclodextrin is directly demonstrable from the following proton magnetic resonance experiment.
Using a standard pulse sequence for Rotating frame Overhauser Enhancement spectroscopy (ROESY) in the TPPI mode, two dimensional spectra of the sample were acquired with a time domain of 256 using a 150 millisecond spin locking pulse and 112 scans. The ROESY experiment reveals through space proton correlations for those protons which are spatially close (< 4 Angstrom). It is well known that the 3' and 5' protons of beta cyclodextrins are oriented towards the centre of the cavity, whereas the 1', 2', 4' and 6' protons are oriented outside the cavity (see Figure 1). Molecular inclusion may thus be directly demonstrated by distance dependant magnetization transfer between propofol protons and the 3', 5' cyclodextrin protons. The assigned two dimensional ROESY spectrum of the complex reveals through space coupling between the magnetically equivalent isopropyl methyl protons of propofol (D,D') and the 3', 5' protons of 2- hydroxypropyl-beta-cyclodextrin as shown in Figure 3. The spectrum thus shows through space correlations between protons separated by a distance of less than 4 Angstrom providing evidence of inclusion complexation. The intensity of the cross peaks is related to the inteπnolecular interproton distance and thus the nature of the inclusion interaction may be modeled as shown in Figures 4a-c. The structure shown in figure 4a was obtained by
initial molecular mechanics energy minimisation of the X-ray crystallographic based structure of beta-cyclodextrin and a computer generated structure of propofol in energy optimised confirmation whereby the 2-cyclodextrin molecules were allowed to complex with each isopropyl moiety respectively in a trimolecular energy minimisation routine. The commercial molecular modelling software HyperChem™ was used for the calculations and drawings. Owing to the bulky nature of the isopropyl substituents a 1: 1 mol/mol stoichiometry would leave a significant hydrophobic protuberance out of the cavity resulting in lower aqueous solubility compared to the 1 :2 mol/mol stoichiometry in which the entire propofol molecule is encapsulated as shown in Figure 4b.
Example 2
In an aseptic processing environment 15,82 g 2-hydroxypropyl-beta- cyclodextrin D.S 4,6 (Janssen Biotech) is weighed and transferred to a sterile graduated mixing vessel. Water for injection (20) ml is added with stirring. Stirring is continued until a clear solution is obtained. The solution is warmed to 45 °C One gram of propofol (Ethyl Corporation) is drawn up into a syringe. The propofol is gradually introduced over a 5 minute period to the concentrated 2-hydroxypropyl-beta-cyclodextrin solution with vigourous stirring. The heat is removed and stirring is continued. When ambient temperature is attained the solution is gradually brought to volume (100 ml) by the addition of aliquots of water for injection with vigorous stirring. Prior to final volume adjustment glycerol is added with stirring to adjust osmolality to 280 - 320 mOsm/kg. The solution is stirred for 10 minutes and bubbled with sterile nitrogen for 20 minutes. The solution is passed through 0,22 micron filter into presterilized glass ampoules. The ampoules are optionally sealed under nitrogen. Propofol content is verified by HPLC analysis to be 10,0 ± 0,1 mg propofol per ml. The clarity of
solution is determined by transmittance spectrophotometry at a wavelength of 800 nanometres and found to be 99,9 %. The solution is stable for at least one month.
Example 3
In an aseptic processing environment 31,64 g 2-hydroxypropyl-beta- cyclodextrin D.S 4,6 (Janssen Biotech) is weighed and transferred to a graduated mixing vessel. Water for injection (40) ml is added with stirring. Stirring is continued until a clear solution is obtained. The solution is warmed to 45 °C Two grams of propofol (Ethyl Corporation) is drawn up into a syringe. The propofol is gradually introduced over a 5 minute period to the concentrated 2-hydroxypropyl-beta-cyclodextrin solution with vigourous stirring. The heat is removed and stirring is continued. When ambient temperature is attained the solution is gradually brought to volume (100 ml) by the addition of aliquots of water for injection with vigorous stirring. The solution is stirred for 10 minutes and the osmolality of the solution is measured (380 ± 20 mOsm/kg). The solution is stirred for 10 minutes and bubbled with sterile nitrogen for 20 minutes. The solution is passed through 0,22 micron filter into presterilized glass ampoules. The ampoules are optionally sealed under nitrogen. Propofol content is verified by HPLC analysis to be 20,0 ± 0,2 mg propofol per ml. The clarity of solution is determined by transmittance spectrophotometry at a wavelength of 800 nanometres and found to be 99,9 %. The solution is stable for at least one month.
Example 4
In an aseptic processing environment 14,63 g 2-hydroxypropyl-beta- cyclodextrin D.S 4,6 (Janssen Biotech) is weighed and transferred to a graduated mixing vessel. Water for injection (20) ml is added with stirring.
Stirring is continued until a clear solution is obtained. The solution is warmed to 45 °C One gram of propofol (Ethyl Corporation) is drawn up into a syringe. The propofol is gradually introduced over a 5 minute period to the concentrated 2-hydroxypropyl-beta-cyclodextrin solution with vigourous stirring. The heat is removed and stirring is continued. When ambient temperature is attained 3g of glycerol is added with stirring and the solution is stirred for 5 minutes. The solution is gradually brought to volume (100 ml) by the addition of aliquots of water for injection with vigorous stirring. The solution is stirred for 10 minutes and bubbled with sterile nitrogen for 20 minutes. The solution is passed through 0,22 micron filter into presterilized glass ampoules. The ampoules are optionally sealed under nitrogen. Propofol content is verified by HPLC analysis to be 10,0 ± 0,1 mg propofol per ml. The clarity of solution is determined by Transmittance spectrophotometry at a wavelength of 800 nanometres and found to be 99,9 %. The solution is stable for at least two weeks.
Example 5
In an aseptic processing environment 14,63 g 2-hydroxypropyl-beta- cyclodextrin D.S 4,6 (Janssen Biotech) is weighed and transferred to a graduated mixing vessel. Water for injection (20) ml is added with stirring. Stirring is continued until a clear solution is obtained. The solution is warmed to 45 °C One gram of propofol (Ethyl Corporation) is drawn up into a syringe. The propofol is gradually introduced over a 5 minute period to the concentrated 2-hydroxypropyl-beta-cyclodextrin solution with vigourous stirring. The heat is removed and stirring is continued. When ambient temperature is attained 10 g of Polyethylene glycol 300 is added with stirring and the solution is stirred for 5 minutes. The solution is gradually brought to volume (100 ml) by the addition of aliquots of water for injection with vigorous stirring. The solution is stirred for 10 minutes
and bubbled with sterile nitrogen for 20 minutes. The solution is passed through 0,22 micron filter into presterilized glass ampoules. The ampoules are optionally sealed under nitrogen. Propofol content is verified by HPLC analysis to be 10,0 ± 0,1 mg propofol per ml. The clarity of solution is determined by transmittance spectrophotometry at a wavelength of 800 nanometres and found to be 99,9 %. The solution is stable for at least two weeks.
Example 6
In an aseptic processing environment, 1000 ml water for injection is heated to 45°C 1023g 2-hydroxypropyl-beta-cyclodextrin D.S 4,6 (Janssen Biotech) is weighed and added to the water for injection with stirring. Stirring is continued until a clear solution is obtained. 52,0 grams of propofol (Ethyl Corporation) is drawn up into a syringe. The propofol is gradually introduced over a 5 minute period to the concentrated 2-hydroxypropyl-beta- cyclodextrin solution with vigorous stirring using a homogenizer. The heat is removed and stirring is continued for 30 minutes. When ambient temperature is attained the solution is gradually brought to volume (5000 ml) by the addition of aliquots of water for injection with vigorous stirring. The solution is stirred for 20 minutes. The solution is stirred and bubbled with sterile nitrogen until the oxygen concentration is below 0,5 mg/1. The solution is passed through 0,22 micron filter into presterilized glass ampoules. The ampoules are optionally sealed under nitrogen. Propofol content is verified by HPLC analysis to be 10,0 ± 0,5 mg propofol per ml.
The compositions of Examples 2 to 6 may be used either as compositions for injection or as compositions for use as retention enemas, as described above.
Claims
A method of preparing a pharmaceutical composition for administration as an injection or as a retention enema, comprising an inclusion complex of propofol and 2-hydroxypropyl-beta-cyclodextrin with approximately a 1:2 mol/mol stoichiometry, includes the steps of:
(a) dissolving in water an amount of 2-hydroxypropyl-beta- cyclodextrin and then adding, with mixing, an amount of propofol to provide an approximate molar ratio of propofol to 2-hydroxypropyl-beta-cyclodextrin of 1 :2 to 1 :2,5, to produce a clear colourless solution; and
(b) if necessary adjusting the osmolality of the solution by adding a pharmaceutically acceptable osmolality adjustment agent.
A method according to claim 1 wherein in step (a) the temperature at which dissolution takes place is between ambient temperature and an elevated temperature up to about 50°C
A method according to claim 1 or claim 2 wherein in step (a), the propofol is introduced in a controlled manner over a period of time with vigorous mixing to the solution containing the calculated amount of 2-hydroxypropyl-beta-cyclodextrin.
A method according to any one of claims 1 to 3 wherein the average degree of substitution of the 2-hydroxypropyl-beta-cyclodextrin used is between 2,5 and 9,0 2-hydroxypropyl groups per beta-cyclodextrin molecule.
A method according to claim 4 wherein the average degree of substitution of the 2-hydroxypropyl-beta-cyclodextrin used is between 3,9 and 5,1 2-hydroxypropyl groups per beta-cyclodextrin molecule.
A method according to any one of claims 1 to 5 wherein in step (b) the pharmaceutically acceptable osmolility adjustment agent is selected from the group consisting of glycerol, dextrose, mannitol and sorbitol.
A method of preparing a pharmaceutical composition for administration as an injection or as a retention enema, comprising an inclusion complex of propofol and 2-hydroxypropyl-beta-cyclodextrin with a stoichiometry of approximately 1 :2 mol/mol, includes the steps of:
(1) dissolving in water an amount of 2-hydroxypropyl-beta- cyclodextrin and then adding, with mixing, an amount of propofol to provide an approximate molar ratio of propofol to 2-hydroxypropyl-beta-cyclodextrin of between 1 :1,5 and 1:<2, and then adding a pharmaceutically acceptable co- solvent, to produce a clear colourless solution.
A method according to claim 7 wherein in step (1) the temperature at which dissolution takes place is between ambient temperature and an elevated temperature up to about 50°C
A method according to claim 7 or claim 8 wherein in step (1) the propofol is introduced in a controlled manner over a period of time with vigorous mixing to the solution containing the calculated amount of 2-hydroxypropyl-beta-cyclodextrin.
A method according to any one of claims 7 to 9 wherein the average degree of substitution of the 2-hydroxypropyl-beta-cyclodextrin used is between 2,5 and 9,02-hydroxypropyl groups per beta-cyclodextrin molecule.
A method according to claim 10 wherein the average degree of substitution of the 2-hydroxypropyl-beta-cyclodextrin used is between 3,9 and 5,1 2-hydroxypropyl groups per beta-cyclodextrin molecule.
A method according to any one of claims 7 to 11 wherein in step (1) the pharmaceutically acceptable co-solvent is selected from the group consisting of glycerol, a glycol, a macrogol or a water soluble polymeric organic compound.
A pharmaceutical composition for administration as an injection or as a retention enema comprising a clear colourless aqueous solution of an inclusion complex of propofol and 2-hydroxypropyl-beta- cyclodextrin with approximately a 1 :2 mol mol stoichiometry.
A pharmaceutical composition for administration as an injection or as a retention enema comprising a clear colourless aqueous solution of an inclusion complex of propofol and 2-hydroxypropyl-beta- cyclodextrin with approximately a 1 :2 mol/mol stoichiometry, which pharmaceutical composition is prepared by:
(i) dissolving in water an amount of 2-hydroxypropyl-beta- cyclodextrin and then adding, with mixing, an amount of propofol to provide an approximate molar ratio of propofol to 2-hydroxypropyl-beta-cyclodextrin of 1 :2 to 1:2,5 to produce a clear colourless solution; and
(ii) if necessary adjusting the osmolality of the solution by adding a pharmaceutically acceptable osmolality adjustment agent.
A pharmaceutical composition for administration as an injection or as a retention enema comprising a clear colourless aqueous solution of an inclusion complex of propofol and 2-hydroxypropyl-beta- cyclodextrin with approximately a 1 :2 mol/mol a stoichiometry and a pharmaceutically acceptable co-solvent.
A pharmaceutical composition for administration as an injection or as a retention enema comprising a clear colourless aqueous solution of an inclusion complex of propofol and 2-hydroxypropyl-beta- cyclodextrin with a stoichiometry of approximately 1:2 mol/mol, and a pharmaceutically acceptable co-solvent, which pharmaceutical composition is prepared by:
(i) dissolving in water an amount of 2-hydroxypropyl-beta- cyclodextrin and then adding, with mixing, an amount of propofol to provide an approximate molar ratio of propofol to 2-hydroxypropyl-beta-cyclodextrin of between 1:1,5 and 1 :<2, and then adding the pharmaceutically acceptable co- solvent, to produce the clear colourless solution.
A pharmaceutical composition according to claim 15 or claim 16 wherein the pharmaceutically acceptable co-solvent is selected from the group consisting of glycerol, glycol, a macrogol, or a water soluble polymeric organic compound.
A pharmaceutical composition according to any one of claims 13 to 17 wherein the composition has a concentration of propofol of at
least 5 mg/millilitre.
A pharmaceutical composition according to claim 18 wherein the composition has a concentration of propofol of about 10 to 20 mg/millilitre inclusive.
A pharmaceutical composition according to any one of claims 13 to 19 formulated in unit dose form, each unit dose containing from 50 to 400 mg inclusive of propofol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU51550/96A AU5155096A (en) | 1995-04-10 | 1996-03-27 | Pharmaceutical composition |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA952938 | 1995-04-10 | ||
| ZA95/2938 | 1995-04-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996032135A1 true WO1996032135A1 (en) | 1996-10-17 |
Family
ID=25584993
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1996/000737 WO1996032135A1 (en) | 1995-04-10 | 1996-03-27 | Pharmaceutical composition |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU5155096A (en) |
| WO (1) | WO1996032135A1 (en) |
| ZA (1) | ZA962214B (en) |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6326406B1 (en) | 1997-05-26 | 2001-12-04 | Westy Ag | Clear, injectable formulation of an anesthetic compound |
| WO2001097796A1 (en) * | 2000-06-21 | 2001-12-27 | Bharat Serums & Vaccines Ltd. | Clear aqueous anaesthetic composition |
| US6551584B2 (en) | 2000-10-10 | 2003-04-22 | Pharmacia & Upjohn Company | Topical antibiotic composition for treatment of eye infection |
| WO2003063824A2 (en) * | 2002-02-01 | 2003-08-07 | Shimoda Biotech (Pty) Ltd | Pharmaceutical composition |
| EP1383445A1 (en) * | 2001-03-20 | 2004-01-28 | Cydex Inc. | Formulations containing propofol and a sulfoalkyl ether cyclodextrin |
| US6887866B2 (en) | 2002-01-25 | 2005-05-03 | Theravance, Inc. | Short-acting sedative hypnotic agents for anesthesia and sedation |
| WO2005067905A1 (en) * | 2004-01-14 | 2005-07-28 | Otsuka Pharmaceutical Factory, Inc. | Propofol-containing fat emulsion preparation |
| US6989381B2 (en) | 2000-08-22 | 2006-01-24 | Pharmacia Corporation | Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading |
| US7034013B2 (en) | 2001-03-20 | 2006-04-25 | Cydex, Inc. | Formulations containing propofol and a sulfoalkyl ether cyclodextrin |
| WO2007052295A3 (en) * | 2005-08-12 | 2007-07-26 | Bharat Serums & Vaccines Ltd | Aqueous anaesthetic compositions comprising propofol |
| US7790766B2 (en) | 2003-07-23 | 2010-09-07 | Theravance, Inc. | Pharmaceutical compositions of short-acting sedative hypnotic agent |
| EP2484350A1 (en) * | 2011-02-04 | 2012-08-08 | Roewer, Norbert, Univ.-Prof. Dr. med. | Pharmaceutical preparation containing a complex of a salt of propofol and a cyclodextrin |
| WO2013078500A1 (en) | 2011-11-29 | 2013-06-06 | Jurox Pty Ltd | Methods of preserving injectable pharmaceutical compositions comprising a cyclodextrin and a hydrophobic drug |
| US9925274B2 (en) | 2012-11-15 | 2018-03-27 | Sapiotec Gmbh | Delphinidin complex as an antiphlogistic or immunosuppressive active ingredient |
| US9949947B2 (en) | 2012-12-11 | 2018-04-24 | Sapiotec Gmbh | Delphinidin for combating melanoma cells |
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| WO1993017711A1 (en) * | 1992-03-11 | 1993-09-16 | Australian Commercial Research & Development Limited | New cyclodextrins and new formulated drugs |
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- 1996-03-19 ZA ZA962214A patent/ZA962214B/en unknown
- 1996-03-27 AU AU51550/96A patent/AU5155096A/en not_active Abandoned
- 1996-03-27 WO PCT/GB1996/000737 patent/WO1996032135A1/en active Application Filing
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| WO1993017711A1 (en) * | 1992-03-11 | 1993-09-16 | Australian Commercial Research & Development Limited | New cyclodextrins and new formulated drugs |
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| WO2001097796A1 (en) * | 2000-06-21 | 2001-12-27 | Bharat Serums & Vaccines Ltd. | Clear aqueous anaesthetic composition |
| JP2003535893A (en) * | 2000-06-21 | 2003-12-02 | ブハラット セルムズ アンド ヴァクシンズ リミテッド | Transparent aqueous anesthetic composition |
| US7138387B2 (en) * | 2000-06-21 | 2006-11-21 | Bharat Serums And Vaccines Limited | Clear aqueous composition comprising propofol and hydroxypropyl-beta-cyclodextrin |
| US6989381B2 (en) | 2000-08-22 | 2006-01-24 | Pharmacia Corporation | Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading |
| US6551584B2 (en) | 2000-10-10 | 2003-04-22 | Pharmacia & Upjohn Company | Topical antibiotic composition for treatment of eye infection |
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Also Published As
| Publication number | Publication date |
|---|---|
| ZA962214B (en) | 1996-10-07 |
| AU5155096A (en) | 1996-10-30 |
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