Title of Invention	NOVEL COMPOSITIONS FOR IMPROVED DELIVERY OF DRUGS WITH POOR AQUEOUS SOLUBILITY
Abstract	The present invention describes novel preconcentrate pharmaceutical compositions containing propofol, cefpodoxime proxetil and triclosan alongwith various pharmaceutically acceptable excipients such as surfactants, solubilisers, stabilisers, oils and modified oils either alone or in combination yielding propofol in stable, solubilized and ready to administer injectable form, on dilution with sterile water for injection and cefpodoxime proxetil and triclosan in microemulisified or nanoemulsified form on dilution with distilled water and buffers.

Title of Invention

NOVEL COMPOSITIONS FOR IMPROVED DELIVERY OF DRUGS WITH POOR AQUEOUS SOLUBILITY

Abstract

The present invention describes novel preconcentrate pharmaceutical compositions containing propofol, cefpodoxime proxetil and triclosan alongwith various pharmaceutically acceptable excipients such as surfactants, solubilisers, stabilisers, oils and modified oils either alone or in combination yielding propofol in stable, solubilized and ready to administer injectable form, on dilution with sterile water for injection and cefpodoxime proxetil and triclosan in microemulisified or nanoemulsified form on dilution with distilled water and buffers.

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 200.3 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "Novel compositions for improved delivery of drugs with poor aqueous solubility" 2. APPLICANT (S) (a) NAME: NAGARSENKER, MANGAL SHAILESH (b)NAT10NALITY: INDIAN (c) ADDRESS: A-401, Vikas Palms, Ambedkar Road, Thane (West) - 400 602 Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Technical field of the invention: The present invention relates to an easily reconstitutable, novel pre-concentrate pharmaceutical compositions capable of providing active pharmaceutical ingredients in solubilized form either in situ with the biological fluid of the body or with distilled water and buffers. The present invention further relates to compositions which are designed with the aim of improving delivery of pharmaceutical active ingredients with poor aqueous solubility. More particularly, the present invention relates to the improved parenteral delivery of Propofol, and improvement in cefpodoxime proxetil and triclosan delivery. Background and prior art: Identifying the strategies for efficient delivery of hydrophobic drugs in order to improve their therapeutic performance has always been a mainstay of drug delivery research and their importance would continue to increase; as approximately 40% or more of the new chemical entities being generated through drug discovery programmes are poorly water- soluble. Solubilization is one way of improving the delivery Of hydrophobic drugs, which has been extensively investigated by the pharmaceutical scientists. In particular, colloidal delivery systems such as microemulsions and nanoemulsions have gained a great interest in the last two decades. Propofol falls under the pharmaceutical category Of anesthetic agents. Chemically Propofo! of formula I is 2,6-diisopropylphenol with the molecular formula C12H18O and its molecular weight is 178.27. Its chemical structure is, as follows: 2 . Propofol is commonly used both for anesthesia and for sedation. It is the intravenous anesthetic of choice for ambulatory surgery in outpatients. Propofot has low water solubility, therefore it must be administered in the form of a lipid emulsion. Due to its high lipid-solubility, Propofol was initially formulated as a solution with the surfactant Cremophore EL, but the occurrence of pain on injection and anaphylactoid reactions prompted to search for alternative formulations. US patent no, 5714520 claims oil in water emulsion of Propofol for parenteral administration comprising a water-immiscible solvent such as a vegetable oil, a surfactant from a natural source, disodium edetate and water. WO9632135 discloses a pharmaceutical composition containing an inclusion complex of Propofol and a cyclodextrin for administration as an injection. GB1472793 discloses compositions in the form of aqueous or non-aqueous compositions, solid or semi-solid mixtures and oil-in-water emulsions of Propofol comprising surfactants, solubilising agents, additional solvents, stabilizers, preservatives, anti- oxidants, sequestering agents and other excipients. Cefpodoxime proxetil (CFP) is an orally absorbed, broad spectrum, third generation cephalosporin ester implicated in treatment of upper respiratory tract and urinary tract infections. 3 Cefpodoxime proxetil of Formula II is RS)-l(isopropoxycarbonyloxy)ethyI (+)-(6R,7R)- 7-[2-(2-amino-4-thiazolyl)-2-[(Z)methoxyirnino] acetamido]-3- methoxymethyl-8-oxo-5- thia-1-azabicyclo [4.2.0]oct-2-ene-2- carboxylate with the molecular formula C21H27NsO9S2 and molecular weight 557.59. Its chemical structure is as follows: Cefpodoxime proxetil has low oral bioavailability (50%) due to hydrolysis by cholinesterases in intestinal lumen. It has low aqueous and pH dependant solubility. Lipid based systems like submicronic emulsions have shown to improve the bioavailability of Cefpodoxime proxetil. Though submicronic emulsion is an attractive approach, the quantity of submicronic emulsions required for administration of single dose of cefpodoxime proxetil and palatability related issues associated with Cefpodoxime proxetil and lipid excipients could be limiting factors for patient compliance and their commercial viability. Hence, there is a strong need for development of lipid- based drug delivery strategy that will retain all the bioavailability related advantages associated with the submicronic emulsion and at the same time would overcome limitations associated with submicronic emulsion. Triclosan (TC) is a poorly water-soluble nonionic compound with broad-spectrum antibacterial/ariti-microbial activity. Triclosan of Formula III is 5-chloro-2-(2,4-dichlorophenoxy)phenol) with the molecular formula C12H7Cl3O2. Its chemical structure is as follows: Triclosan is used in the treatment of plaque, caries and gingivitis. Moreover, triclosan has also shown to have anti-acne and anti-malarial activity. Triclosan appears to kill bacteria mainly by inhibiting fatty acid synthesis. Triclosan binds to bacterial enoyl-acyl carrier protein reductase enzyme (ENR), which is encoded by Fabl. This binding increases the enzyme's affinity for nicotinamide adenine 4 dinucleotide (NAD+), This results in the formation of a stable ternary complex of Fabl- NAD+-triclosan, which is unable to participate in fatty acid synthesis. Fatty acid is necessary for reproducing and building cell membranes. Humans do not have an ENR enzyme, and thus are not affected. Some bacterial strains are resistant to triclosan due to FabI mutations which decrease triclosan's effect on FabI-NAD+ binding. Object of the invention: The Object of the present invention relates to an easily reconstitutable, novel pre- concentrate pharmaceutical compositions capable of providing active pharmaceutical ingredients in solubilized form either in situ with the biological fluid of the body or with distilled water and buffers. Another object of the invention provides compositions which are designed with the aim of improving delivery of pharmaceutical active ingredients with poor aqueous solubility. Yet another object of the invention relates to the improved parenteral delivery of Propofol, and improvement in cefpodoxime proxetil and triclosan delivery. Further object of the invention is to overcome the disadvantages like hyperlipidemia, poor physical stability, embolism and pain at injection site associated with the currently marketed Propofol formulations. In a further object of the invention, the use of preconcentrate is also extended to deliver Cefpodoxime proxetil and triclosan in solubilized form for improving their oral and/or dermal delivery. Summary of the invention: The present invention describes an easily reconstitutable, novel pre-concentrate pharmaceutical compositions capable of providing active pharmaceutical ingredients in solubilized form either in situ with the biological fluid of the body or with distilled water and buffers. The present invention further describes compositions which are designed 5 with the aim of improving delivery of pharmaceutical active ingredients with poor aqueous solubility. More particularly, the present invention describes the improved parenteral delivery of Propofol, and improvement in cefpodoxime proxetil and triclosan delivery. The present invention more particularly describes pharmaceutical compositions for parenteral administration in the form of novel preconcentrates containing Propofol and various pharmaceutically acceptable excipients such as surfactants, solubilisers, stabilisers, oils and modified oils either alone or in combination yielding Propofol in stable, solubilized and ready to administer injectable form, on dilution with sterile water for injection or other vehicles such as 0.9% saline, 2.25% glycerine, 5% dextrose and 5 % sorbitol. Further, the invention describes preconcentrates prepared with pharmaceutically acceptable excipients such as surfactants, co-surfactants, solubilisers, stabilisers, oils and modified oils either alone or in combination that can yield cefpodoxime proxetil and triclosan in microemulisified or nanoemulsified form on dilution with distilled water and buffers. Detailed description of the invention: The present invention describes novel pharmaceutical preconcentrates designed for improved delivery of hydrophobic drugs with special emphasis on Propofol, Cefpodoxime proxetil and Triclosan. Moreover, the compositions described herein could be employed for parenteral or oral or dermal delivery of active pharmaceutical ingredients depending upon the ingredients used in their preparation. Propofol, 2,6-diisopropylphenol, is a short-acting anesthetic agent, administered by intravenous route for short surgical procedures, mechanical ventilation in the intensive care unit. Propofol is poorly water soluble. It is very popular amongst clinicians due to its favorable pharmacokinetic profile, rapid onset and recovery even after long periods of anesthesia and low incidence of post-operative nausea and vomiting. However, its poor 6 aqueous solubility poses a challenge to formulation scientists which the present inventors have tried to overcome. Cefpodoxime proxetil is a poorly bioavailable, high dose cephalosporin antibiotic having pH dependant solubility and poor aqueous solubility, Triclosan (TC) is a broad-spectrum antibacterial/anti-microbial agent and has poor water solubility, which makes it difficult to formulate. However, its poor aqueous solubility poses a challenge to formulation scientists which the present inventors have tried to overcome. The present inventors have provided preparation of preconcentrates which can present the drug in solubilized form thereby improving delivery of propofol, cefpodoxime proxetil and triclosan by various routes of administration such as parenteral, oral, buccal or dermal depending upon their relevance and the indication of the drug. The present investigation describes the development and evaluation of novel preconcentrates for improving the delivery of Propofol, Cefpodoxime proxetil and Triclosan, They comprise Propofol or cefpodoxime proxeti] or triclosan and suitable surfactants, co-surfactants, solubilizers, stabilizers, oils and modified oils used alone or in combination to formulate pharmaceutically acceptable systems. Furthermore, the compositions thus obtained could be liquid, semi-solid or solid depending upon the ingredients used for their preparation. Compositions of the present invention consists of surfactants selected from the group consisting of polyethylene glycol-15-hydroxystearate (Solutol HS 15™), polyoxyethylene sorbitan esters such as polysorbate 80, polysorbate 20, Cg-Cjo polyglycolized glycerides (Gelucires™), Lecithins, Hydrogenated lecithins, modified lecithins (Lecinol SHE 50™), Polyoxyethylene alky] ethers (Brij 97 ™, Brij 96V ™, Brij 35 ™, Brij 78™, Brij 58™, BL9EX™) , Poloxamers, Capryl-caproyl macrogol-8 glyceride (Labrasol™), 7 Polyethyleneglcoylated castor oil (Cremophore EL) and Polyethyleneglycolated hydrogenated castor oil (Cremophore RH-40) either alone or in combination. Compositions of the present invention further contain co-surfactants or solubilizers selected from the group of Ethanol, Glycofurol, Tetraglycol, Isopropanol, Propylene glycol, Polyethylene glycol, Glycerol, Diethylene glycol monoethyl ether (Transcutol™ or Carbitol), Benzyl alcohol, Dimethyl acetamide, N-methyl pyrrol idone, 2-PyrroIidone (Soluphore™) Polyvinyl pyrrolidone, capric-caprylic mono, di and tri glycerides marketed under trade name of Akoline, Sefsol, Akonons, Myvacets, and Capmul either alone or in combination. Further the compositions contain stabilizers like sodium metabisulphite, EDTA, sodium ascorbate, sodium lactate, butylated hydroxy anisole, alanine, proline, butylated hydoxy toluene either alone or in combination. Compositions also contain oils and modified oils like soyabean oil, com oil, rice bran oil, arachis oil, sunflower oil, sesame oil, peppermint oil, lime oil, ethyl oleate, benzyl benzoate, ethyl linoleate, triacetin, ethyl laurate, propylene glycol monocaprylate (Capryol 90™, Capryol PGMC™, Sefsol 218™), Polyethyleneglycol 6-esters (Labrafil 1944 CS), isopropyl myristate, oleic acid, medium chain triglycerides, capric-capryiic, lauric or oleic mono, di and tri glycerides marketed under trade name of Labrafils, Labrafacs, Lauroglycols, Plurols, Akoline, Akomed, Akonons, Myvacets, Captex and Capmul either alone or in combination. The present investigation is more specifically explained by following examples. However, it should be understood that that.the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present investigation includes the following examples and further can be modified and altered within the technical concept of the present investigation. 8 EXAMPLES Example 1: SolutolHS 15 12-20 gms. Propofol 1 gm. Sterile Water for injection (SWFI) or 0.9% saline q.s. 100 gms. Example 2: SolutolHS 15 8-12gm Polysorbate 80 1-5gm Propofol 1 gm. SWFI or 0.9% saline q.s. 1oo gms. Example 3: Solutol HS 15 8-12gm Propylene glycol 1-5gm Propofol 1 gm. SWFI or 0.9% saline q.s. 100 gms. Example 4: Solutol HS 15 8-12gm Glycofurol 1-5gm Propofol 1 gm. SWFI or 0.9% saline q.s. 100 gms. Example 5: SolutolHS 15 8-12gm EihanoJ 1-5gm Propofol 1-gm SWFI or 0.9% saline q.s. 100 gms. 9 Example 6: SolutolHS 15 4-12gm BL9EX l-5gm Propofol 1 gm. SWFI or 0.9% saline q.s. 100 gms. Example 7: BL9EX 7-15gm Propofol 1 gm. SWFI or 0.9% saline q.s. 100 gms. Example 8: Solutol HS 15 8-12gm Labrasol l-4gm Propofol 1 gm. SWFI or 0.9% saline q.s. 100 gms. Example 9: SolutolHS 15 8-12gm Lecinol SHE 50 1-5 gms Propofol 1 gm. SWFI or 0.9% saline q.s. 100 gms. The compositions described in the aforementioned examples can be prepared by mixing all the ingredients except aqueous phase (SWFI or 0.9% saline) with the help of gentle heat (60°C) to effect a homogenous solution. These compositions can be stored as preconcentrate in a suitable glass vial and can be diluted with SWFI or 0.9%saline whenever required to yield Propofol (l%w/w) in solubilized form. The compositions can also be diluted with other vehicles such as 2.25% glycerol, 5% dextrose and 5% sorbitol. 10 Example 10: Lecinol SHE 50 8-15gm BL9EX 5-10gm Triclosan 1gm Capryol90 l-4gm Distilled Water q.s. 1 OOgm Triclosan is first dissolved in Capryol 90 with the help of magnetic stirring. TO this oily solution Lecinol SHE 50 and BLEX are added. This preconcentrate after dilution with water or buffer spontaneously yields microemulsion with globule size less than 200nm. Example 11: Cremophore EL 0.1-0.4gm Capryol 90 0.2-0.4gm Cefpodoxime proxetil 0.13gm Example 12: Solutol HS 15 0.2-0.4gm Capmul MCM C-8 0.1-0.4gm Cefpodoxime proxetil 0.13gm Example 13: Polysorbate 20 0.2-0.4gm Labrafil 1944 CS 0.05-0.15gm Capryol 90 0.1-0.4gm Cefpodoxime proxetil 0.13gm Example 14: PoloxamerlSS 0.2-0.4gm Capryol 90 0.1-0.4gm Cefpodoxime proxetil 0.13gm 11 Example 15: Poloxamer 407 0.2-0.4gm Capryol 90 0.1-0.4gm Cefpodoxime proxeti 1 0.13 gm Example 16: Cremophore EL 0.2-0.4gm Akoline MCM 0.05-0.15gm Capryol 90 0.1-0.4gm Cefpodoxime proxetil 0.13gm Example 17: Cremophore EL 0.2-0.4gm Gelucire 44/14 0.05-0.15gm Capryol 90 0.1-0.4gm Cefpodoxime proxetil 0.13gm The compositions described in the examples 11 to 17 can be prepared by first dissolving Cefpodoxime proxetil in oily phase with the help of magnetic stirring and then by adding the remaining ingredient followed by gentle heating at 60°C (whenever required) to yield a homogenous preconcentrate. These preconcentrates would yield microemulsions or nanoemulsions after dilution with distilled water or physiological buffers. These preconcentrates can be filled in hard gelatin or soft gelatin capsules or can be adsorbed onto solid carriers to obtain a unit dosage form. These compositions after ingestion would present Cefpodoxime proxetil in nanoemulsified form in vivo. Various experiments performed with some selected compositions would be presented herein. In all the experiments related to Propofol, compositions described in Examples 2,3 and 4 are used. In all the experiments related cefpodoxime proxetil, composition described in Example 16 is used. 12 Experiment 1 Globule size of Propofol: The compositions described in Examples 2,3 and 4 were diluted suitably with 0.9% saline and the globule size of Propofol was determined by using photon correlation spectroscopy (PCS). The globule size of Propofol was found to be less than 30nm in all the cases. Moreover, there was no considerable increase in the globule size on storing the microemulsions for 18 hrs confirming their suitability for IV infusion of Propofol. Experiment 2: pH determination: The compositions described in Examples 2,3 and 4 were prepared and their pH was determined in triplicate at room temperature. The compositions exhibited pH in the range of 4.7-5.1 Experiment 3: Effect of centrifugation and freeze-thaw cycling: The compositions described in Examples 2,3 and 4 were prepared. The compositions were centrifuged at 5000 rpm for 20 min to assess effect of centrifugation. Furthermore, compositions were subjected to freeze-thaw cycling. One freeze-thaw cycle consisted of storing of compositions at -20°C for 24 h. After this, they were stored at room temperature for another 24 hrs. Compositions could withstand centrifugation and freeze- thaw cycling. Experiment 4: Effect of autoclaving; The preconcentrates described in Examples 2,3 and 4 were prepared, filled in glass vials, sealed and sterilized by autoclaving at 121°C for 15 min. The effect of autoclaving was f determined by evaluating the Propofol content, globule size and pH of the compositions before and after the autoclaving. Autoclaving did not have any significant effect on the Propofol content, globule size and pH of the compositions. 13 Experiments: In vitro hemolysis: In vitro hemolysis of compositions described in Examples 2, 3 and 4 was assessed using heparinized fresh human whole blood. Blood samples were pooled and subdivided into three portions (1.6 ml each) and each of the portions Was spiked with various Propofol microemulsions (0.4 ml) such that the final concentration of Propofol in all the blood samples was 10 ng/ml. Immediately after addition, the blood-microemulsion mixture was gently agitated for 5-10 seconds and incubated at 37°C for 2 hrs. After incubation, the mixtures were placed in the ice-cold water for 2 min to quench the hemolytic process. The intact red blood cells were separated from the supernatant by centrifugation at 3000 rpm for 5 min at 5°C. The negative control was prepared by incubating 1.6 ml of blood with 0.4 ml of 0.9 % sodium chloride solution at 37°C for 2 h. In order to obtain I00°/0 hemolysis of the blood, 1.6 ml of blood was diluted with 14.4 ml of double distilled water and the mixture was incubated at 37°C for 30min. This sample served as positive control. The controls received same treatment as that of test samples so as to separate intact erythrocytes from the mixture. However, in case of negative control all the erythrocytes remained intact and in case of positive control none of the erythrocytes remained intact. The supernatant from all the samples (including positive and negative control) was removed, transferred to another microcentrifuge tube and centrifuged again at 3000 rpm for 5 min at 5°C in order to get rid of any intact erythrocytes that may have come while withdrawing the supernatant. Supernatant, 0.3 ml was Suitably diluted with 4.15 ml of 0.9% saline in case of test samples and negative control and with double distilled water in case of positive control and analyzed for the content of hemoglobin by measuring the absorbance of supernatant at 540 nm. The extent of hemolysis as percentage (% H) was determined by using following equation % H = [(Abs - Abs control) / (Abs100 - Abs control)X 100 where, Abs is absorbance of sample, Abs control is absorbance of control sample (negative control), Absioo is absorbance of sample in which 100 % hemolysisj occurred (positive control). 14 The compositions led to very negligible hemolysis (less than 1%) even after 2 hrs of contact with blood. Experiment 6: In-vivo anesthetic efficacy In-vivo anesthetic efficacy was carried out to test anesthetic power of the developed Propofol formulations. The efficacy of developed formulations was compared with marketed Propofol emulsion (Propovan™, Bharat Serums Pvt Ltd., Mumbai). Adult female Wistar rats with body mass of 200-250 g, were obtained from Hafflcins Institute, Mumbai at the beginning of the experiments. Rats were maintained under an artificial 12 h light-dark cycle (lights on from 08:00 to 20:00 h) and at a constant temperature of 23 ± 2°C and 65% humidity. Food and water were freely available, and the animals were acclimatized for >7 days before use. Experiments were performed between 08:00 and 14:00 h. Animal care and handling throughout the experimental procedure were performed in accordance to the CPCSEA guidelines. The experimental protocol was approved by the Animal Ethical Committee of the Bombay College of Pharmacy. Rats were injected intravenously (single bolus in the lateral tail vein) with the different formulations of Propofol, each containing equimolar concentration of Propofol [10 mg/(ml kg)]. For intravenous administration, animals were restrained in an appropriate plexiglass cage and a tail vein was used. Following the drug administration, rats (six per treatment group) were observed for the following 60 min, and the onset and duration of loss of the righting reflex (LORR) were recorded. The duration of LORR, expressed as mean ± S.D. was subjected to statistical analysis. The statistical significance of differences in the duration of LORR data were analyzed utilizing analysis of variance (ANOVA) followed by Dunnet's test (GraphPad InStat Demo Version). Differences were considered statistically significant at P 15 The results of the in vivo anesthetic efficacy test are shown below in table 1 Table 1: Comparison of developed Propofol formulation with marketed formulation Duration of LORR (minutes) Animal Propovan™ Example 2 Example 3 Example 4 1 10.57 13.42 13.02 13.48 2 13.22 11.59 13.07 14.24 3 10.41 15.25 15.37 14.17 4 11.21 15.38 15.1 12.08 5 15.05 12.42 17.49 15.38 6 17.05 16.45 18.1 18.1 12.918 ±2.699 14.085 ± 1.9 15 .358 ± 2.136 14.575 ±2.038 Experiment 7: Globule size analysis of cefpodoxime proxetil preconcentrate: Composition described in example 15, 50 mg was diluted to 50 ml with different dilution media viz. double distilled water, buffer pH 1.2, buffer pH 3.0 and pH 6.8 buffer. The mean globule size and size distribution of resulting nanoemulsions was determined using PCS. The globule size of all the nanoemulsions was found to be less than 200nm. The compositions in this investigation can be utilized for the parenteral, peroral, topical delivery of the hydrophobic agents belonging to the therapeutic classes like immunosupressants, anti-viral agents, vitamins, anti-adrenergic agents, adrenergic agents, cholinergic agents, anti-cholinergic agents, anti-migrane agents, anti-parkinsonian agents, anti-alzhimer agents, anti-acne agents, anti-glaucoma agents, steroidal agents, anti- arthritic agents, anti-bacterial agents, anti-malarial agents, anti-parasitic agents, anti- cancer agents, anti-inflammatory agents, diuretic agents, hypoglycemic agents, anti- hyperlipidemic agents, anti-hypertensive agents, anti-fungal agents, anti-histaminics, anti- protozoal agents and others categories comprising of hydrophobic agents. 16 It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. 17 I claim, 1. Pharmaceutical preconcentrate compositions comprising one of the hydrophobic pharmaceutical components, Propofol, Cefpodoxime proxetil and Triclosan as an active ingredient with suitable pharmaceutically acceptable excipients selected from the group consisting of surfactants, co-surfactants, solubilizers, oils or modified oils and stabilizers either alone or in combination. 2. Pharmaceutical preconcentrate compositions of claim 1, wherein Propofol compositions upon dilution with sterile water or 0.9% saline yields solution of Propofol with concentration of l%w/w. 3. Pharmaceutical preconcentrate compositions of Propofol as claimed in claim 1 and claim 2, wherein at least one of the surfactant is selected from the group consisting of polyethylene glycol-15-hydroxystearate (Solutol HS 15), BL9EX, Polyoxyethylene sorbitan esters like Polysorbate 80, Poloxamers like poloxamer 407, Polyoxyethylene alkyl ethers like Brij 58, Lecithis and modified lecithins like Lecinol SHE 50™, Capryl-caproyI macrogol-8 glyceride (Labrasol™) either alone or in combination with with solubilizers and co-surfactants 4. Pharmaceutical preconcentrate compositions of Propofol as claimed in claim 1 and claim 2, wherein at least one of the co-surfactant or solubilizer is selected from the group consisting of ethanol, propylene glycol, glycofurol, glycerol and polyethylene glycol. 5. Pharmaceutical preconcentrate compositions of Propofol as claimed in claim 1 to claim 4, wherein the preconcentrate compositions are prepared by mixing Propofol and surfactant and/or co-surfactant or solubilizer by gentle heating at 60°C to obtain a homogeneous mixture which upon dilution with sterile water or 0.9% saline yield Propofol (l%w/w) in solubilized form with globule size less than 200nm having pH in the range of 4.7 to 5.1. 18 6. Pharmaceutical preconcentrate compositions of claim 1, wherein the hydrophobic pharmaceutical component is Cefpodoxime proxetil and the compositions are prepared by dissolving Cefpodoxime proxetil in oily phase using magnetic stirrer and addition of the surfactants and/or co-surfactants by gentle heating at 60°C to yield a homogeneous preconcentrate in a self nanoemulsified form upon dilution with distilled water or physiological buffer, with globule size less than 200nm 7. Pharmaceutical preconcentrate compositions of Cefpodoxime proxetil as claimed in claim 1 and claim 6, wherein at least one of the surfactant is selected from the group consisting of Polyethylene glycol-15-hydroxystearate (Solutol HS 15), BL9EX, Polyoxyethylene sorbitan esters like Polysorbate 80, Poloxamers like poloxamer 407, Polyoxyethylene alkyl ethers like Brij 58, Lecithis and modified lecithins (Lecinol SHE 50™), Capryl-caproyl macrogoI-8 glyceride (Labrasol™), Castor oil based surfactants such as Polyoxyl 35 Castor Oil (Cremophore EL) and Polyoxyl 40 Hydrogenated Castor Oil (Cremophore RH 40) either alone or in combination with other ingredients. 8. Pharmaceutical preconcentrate compositions of Cefpodoxime proxetil as claimed in claim 1 and claim 6, wherein at least one of the co-surfactant or solubilizer is selected from the group consisting of ethanol, propylene glycol, tetrahydrofurfuryl alcohol polyethylene glycol ether (glycofurol or tetraglycol), glycerol, polyethylene glycol, diethylene glycol monothyl ether (Transcutol™) and medium chain mono-, di-, triglycerides like Akoline, Sefsof, Akonons, Myvacets and Capmuls like Caprylic/Capric Glycerides (Akoline MCM), Medium Chain Mono- & Djglycerides (Capmul MCM) and Glyceryl Monocaprylate (Capmul MCM- C8). 9. Pharmaceutical preconcentrate compositions of Cefpodoxime proxetil as claimed in claim 1 and claim 6, wherein at least one of the oils is selected from the group consisting of soyabean oil, corn oil, rice bran oil, arachis oil, sunflower oil, sesame oil, peppermint oil, lime oil, ethyl oleate, benzyl benzoate, ethyl linoleate, triacetin, ethyl laurate, propylene glycol monocaprylate (Capryol 90™, Capryol 19 PGMC™), Sefsol 218™), Polyethyleneglycol 6-esters (Labrafil 1944 CS), isopropyl myristate, oleic acid, medium chain triglycerldes, capric-caprylic, lauric or oleic mono, di and tri glycerides like Labrafils, Labrafacs, Lauroglycols, Plurals, Akoline, Akomed, Akonons, Myvacets, Captex and Capmul either alone or in combination. 10. Pharmaceutical preconcentrate compositions of claim 1, wherein the hydrophobic pharmaceutical component is Triclosan l%w/w and the compositions are prepared by dissolving Triclosan in modified oil by magnetic stirring and addition of one or more surfactants to this oily mixture which upon dilution with water or buffers yields microemulsified form with globule size less than 200nm, 11. Pharmaceutical preconcentrate compositions of Triclosan as claimed in claim 1 and claim 10, wherein at least one of the surfactant is selected from the group consisting of Polyethylene glycol-15-hydroxystearate (Solutol HS 15), BL9EX, Polyoxyethylene sorbitan esters like Polysorbate 80, Poloxamers like poloxamer 407, Polyoxyethylene aJkyl ethers like Brij 58, Lecithis and modified lecithins (Lecinol SHE 50™), Capryl-caproyl macrogol-8 glyceride (Labrasol™), Castor oil based surfactants such as Polyoxyl 35 Castor Oil (Cremophore EL) and Polyoxyl 40 Hydrogenated Castor Oil (Cremophore RH 40) either alone or in combination with other ingredients. 12. Pharmaceutical preconcentrate compositions of Triclosan as claimed in claim 1 and claim 10, wherein at least one of the co-surfactant or solubilizer is selected from the group consisting of ethanol, propylene glycol, glycofurol, glycerol, polyethylene glycol, diethylene glycol monothyl ether (Transcutol™) and medium chain mono-, di-, triglycerides like Akoline, Sefsol, Akonons, Myvacets and Capmuls like Caprylic/Capric Glycerides {Akoline MCM), Medium Chain Mono- & Diglycerides (Capmul MCM) and Glyceryl Monocaprylate (Capmul MCM- C8). 13. Pharmaceutical preconcentrate compositions of Triclosan as claimed in claim 1 and claim 10, wherein at least one of the oils is selected from the group consisting 20 of soyabean oil, corn oil, rice bran oil, arachis oil, sunflower oil, sesame oil, peppermint oil, lime oil, ethyl oleate, benzyl benzoate, ethyl linoleate, triacetin, ethyl laurate, propylene glycol monocaprylate (Capryol 90™), Sefsol 218™), Polyethyleneglycol 6-esters (Labrafil 1944 CS), isopropyl myristate, oleic acid, medium chain triglycerides, capric-caprylic, lauric or oleic mono, di and tri glycerides like polyoxyethylenated vegetable oils (Labrafils), Labrafacs, Laurogfycols, Plurols, Akoline, caprylic/capric triglyceride(Akomed), Akonons, Acetylated monoglycerides (Myvacets), Captex and Capmul either alone or in combination. 14. Pharmaceutical preconcentrate compositions as claimed in any of the preceding claims 1 to 13, their process of preparation and evaluation as described herein with reference to the foregoing examples 1-17. 21 Dated this 25th day of May 2006

Full Text

FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 200.3
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Novel compositions for improved delivery of drugs with poor aqueous
solubility"
2. APPLICANT (S)
(a) NAME: NAGARSENKER, MANGAL SHAILESH
(b)NAT10NALITY: INDIAN
(c) ADDRESS: A-401, Vikas Palms, Ambedkar Road, Thane (West) - 400 602
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it is to be performed.

Technical field of the invention:
The present invention relates to an easily reconstitutable, novel pre-concentrate
pharmaceutical compositions capable of providing active pharmaceutical ingredients in
solubilized form either in situ with the biological fluid of the body or with distilled water
and buffers. The present invention further relates to compositions which are designed
with the aim of improving delivery of pharmaceutical active ingredients with poor
aqueous solubility. More particularly, the present invention relates to the improved
parenteral delivery of Propofol, and improvement in cefpodoxime proxetil and triclosan
delivery.
Background and prior art:
Identifying the strategies for efficient delivery of hydrophobic drugs in order to improve
their therapeutic performance has always been a mainstay of drug delivery research and
their importance would continue to increase; as approximately 40% or more of the new
chemical entities being generated through drug discovery programmes are poorly water-
soluble.
Solubilization is one way of improving the delivery Of hydrophobic drugs, which has
been extensively investigated by the pharmaceutical scientists. In particular, colloidal
delivery systems such as microemulsions and nanoemulsions have gained a great interest
in the last two decades.
Propofol falls under the pharmaceutical category Of anesthetic agents. Chemically
Propofo! of formula I is 2,6-diisopropylphenol with the molecular formula C12H18O and
its molecular weight is 178.27. Its chemical structure is, as follows:

2 .

Propofol is commonly used both for anesthesia and for sedation. It is the intravenous
anesthetic of choice for ambulatory surgery in outpatients. Propofot has low water
solubility, therefore it must be administered in the form of a lipid emulsion. Due to its
high lipid-solubility, Propofol was initially formulated as a solution with the surfactant
Cremophore EL, but the occurrence of pain on injection and anaphylactoid reactions
prompted to search for alternative formulations.
US patent no, 5714520 claims oil in water emulsion of Propofol for parenteral
administration comprising a water-immiscible solvent such as a vegetable oil, a surfactant
from a natural source, disodium edetate and water.
WO9632135 discloses a pharmaceutical composition containing an inclusion complex of
Propofol and a cyclodextrin for administration as an injection.
GB1472793 discloses compositions in the form of aqueous or non-aqueous compositions,
solid or semi-solid mixtures and oil-in-water emulsions of Propofol comprising
surfactants, solubilising agents, additional solvents, stabilizers, preservatives, anti-
oxidants, sequestering agents and other excipients.
Cefpodoxime proxetil (CFP) is an orally absorbed, broad spectrum, third generation
cephalosporin ester implicated in treatment of upper respiratory tract and urinary tract
infections.
3
Cefpodoxime proxetil of Formula II is RS)-l(isopropoxycarbonyloxy)ethyI (+)-(6R,7R)-
7-[2-(2-amino-4-thiazolyl)-2-[(Z)methoxyirnino] acetamido]-3- methoxymethyl-8-oxo-5-
thia-1-azabicyclo [4.2.0]oct-2-ene-2- carboxylate with the molecular formula
C21H27NsO9S2 and molecular weight 557.59. Its chemical structure is as follows:

Cefpodoxime proxetil has low oral bioavailability (50%) due to hydrolysis by
cholinesterases in intestinal lumen. It has low aqueous and pH dependant solubility.
Lipid based systems like submicronic emulsions have shown to improve the
bioavailability of Cefpodoxime proxetil. Though submicronic emulsion is an attractive
approach, the quantity of submicronic emulsions required for administration of single
dose of cefpodoxime proxetil and palatability related issues associated with Cefpodoxime
proxetil and lipid excipients could be limiting factors for patient compliance and their
commercial viability. Hence, there is a strong need for development of lipid- based drug
delivery strategy that will retain all the bioavailability related advantages associated with
the submicronic emulsion and at the same time would overcome limitations associated
with submicronic emulsion.
Triclosan (TC) is a poorly water-soluble nonionic compound with broad-spectrum
antibacterial/ariti-microbial activity.
Triclosan of Formula III is 5-chloro-2-(2,4-dichlorophenoxy)phenol) with the molecular
formula C12H7Cl3O2. Its chemical structure is as follows:

Triclosan is used in the treatment of plaque, caries and gingivitis. Moreover, triclosan has
also shown to have anti-acne and anti-malarial activity.
Triclosan appears to kill bacteria mainly by inhibiting fatty acid synthesis. Triclosan
binds to bacterial enoyl-acyl carrier protein reductase enzyme (ENR), which is encoded
by Fabl. This binding increases the enzyme's affinity for nicotinamide adenine
4

dinucleotide (NAD+), This results in the formation of a stable ternary complex of Fabl-
NAD+-triclosan, which is unable to participate in fatty acid synthesis. Fatty acid is
necessary for reproducing and building cell membranes. Humans do not have an ENR
enzyme, and thus are not affected. Some bacterial strains are resistant to triclosan due to
FabI mutations which decrease triclosan's effect on FabI-NAD+ binding.
Object of the invention:
The Object of the present invention relates to an easily reconstitutable, novel pre-
concentrate pharmaceutical compositions capable of providing active pharmaceutical
ingredients in solubilized form either in situ with the biological fluid of the body or with
distilled water and buffers.
Another object of the invention provides compositions which are designed with the aim
of improving delivery of pharmaceutical active ingredients with poor aqueous solubility.
Yet another object of the invention relates to the improved parenteral delivery of
Propofol, and improvement in cefpodoxime proxetil and triclosan delivery.
Further object of the invention is to overcome the disadvantages like hyperlipidemia, poor
physical stability, embolism and pain at injection site associated with the currently
marketed Propofol formulations.
In a further object of the invention, the use of preconcentrate is also extended to deliver
Cefpodoxime proxetil and triclosan in solubilized form for improving their oral and/or
dermal delivery.
Summary of the invention:
The present invention describes an easily reconstitutable, novel pre-concentrate
pharmaceutical compositions capable of providing active pharmaceutical ingredients in
solubilized form either in situ with the biological fluid of the body or with distilled water
and buffers. The present invention further describes compositions which are designed
5

with the aim of improving delivery of pharmaceutical active ingredients with poor
aqueous solubility. More particularly, the present invention describes the improved
parenteral delivery of Propofol, and improvement in cefpodoxime proxetil and triclosan
delivery.
The present invention more particularly describes pharmaceutical compositions for
parenteral administration in the form of novel preconcentrates containing Propofol and
various pharmaceutically acceptable excipients such as surfactants, solubilisers,
stabilisers, oils and modified oils either alone or in combination yielding Propofol in
stable, solubilized and ready to administer injectable form, on dilution with sterile water
for injection or other vehicles such as 0.9% saline, 2.25% glycerine, 5% dextrose and 5 %
sorbitol.
Further, the invention describes preconcentrates prepared with pharmaceutically
acceptable excipients such as surfactants, co-surfactants, solubilisers, stabilisers, oils and
modified oils either alone or in combination that can yield cefpodoxime proxetil and
triclosan in microemulisified or nanoemulsified form on dilution with distilled water and
buffers.
Detailed description of the invention:
The present invention describes novel pharmaceutical preconcentrates designed for
improved delivery of hydrophobic drugs with special emphasis on Propofol,
Cefpodoxime proxetil and Triclosan. Moreover, the compositions described herein could
be employed for parenteral or oral or dermal delivery of active pharmaceutical ingredients
depending upon the ingredients used in their preparation.
Propofol, 2,6-diisopropylphenol, is a short-acting anesthetic agent, administered by
intravenous route for short surgical procedures, mechanical ventilation in the intensive
care unit. Propofol is poorly water soluble. It is very popular amongst clinicians due to
its favorable pharmacokinetic profile, rapid onset and recovery even after long periods of
anesthesia and low incidence of post-operative nausea and vomiting. However, its poor
6

aqueous solubility poses a challenge to formulation scientists which the present inventors
have tried to overcome.
Cefpodoxime proxetil is a poorly bioavailable, high dose cephalosporin antibiotic having
pH dependant solubility and poor aqueous solubility,
Triclosan (TC) is a broad-spectrum antibacterial/anti-microbial agent and has poor water
solubility, which makes it difficult to formulate.
However, its poor aqueous solubility poses a challenge to formulation scientists which the
present inventors have tried to overcome.
The present inventors have provided preparation of preconcentrates which can present the
drug in solubilized form thereby improving delivery of propofol, cefpodoxime proxetil
and triclosan by various routes of administration such as parenteral, oral, buccal or dermal
depending upon their relevance and the indication of the drug.
The present investigation describes the development and evaluation of novel
preconcentrates for improving the delivery of Propofol, Cefpodoxime proxetil and
Triclosan, They comprise Propofol or cefpodoxime proxeti] or triclosan and suitable
surfactants, co-surfactants, solubilizers, stabilizers, oils and modified oils used alone or in
combination to formulate pharmaceutically acceptable systems.
Furthermore, the compositions thus obtained could be liquid, semi-solid or solid
depending upon the ingredients used for their preparation.
Compositions of the present invention consists of surfactants selected from the group
consisting of polyethylene glycol-15-hydroxystearate (Solutol HS 15™), polyoxyethylene
sorbitan esters such as polysorbate 80, polysorbate 20, Cg-Cjo polyglycolized glycerides
(Gelucires™), Lecithins, Hydrogenated lecithins, modified lecithins (Lecinol SHE 50™),
Polyoxyethylene alky] ethers (Brij 97 ™, Brij 96V ™, Brij 35 ™, Brij 78™, Brij 58™,
BL9EX™) , Poloxamers, Capryl-caproyl macrogol-8 glyceride (Labrasol™),
7

Polyethyleneglcoylated castor oil (Cremophore EL) and Polyethyleneglycolated
hydrogenated castor oil (Cremophore RH-40) either alone or in combination.
Compositions of the present invention further contain co-surfactants or solubilizers
selected from the group of Ethanol, Glycofurol, Tetraglycol, Isopropanol, Propylene
glycol, Polyethylene glycol, Glycerol, Diethylene glycol monoethyl ether (Transcutol™
or Carbitol), Benzyl alcohol, Dimethyl acetamide, N-methyl pyrrol idone, 2-PyrroIidone
(Soluphore™) Polyvinyl pyrrolidone, capric-caprylic mono, di and tri glycerides
marketed under trade name of Akoline, Sefsol, Akonons, Myvacets, and Capmul either
alone or in combination.
Further the compositions contain stabilizers like sodium metabisulphite, EDTA, sodium
ascorbate, sodium lactate, butylated hydroxy anisole, alanine, proline, butylated hydoxy
toluene either alone or in combination.
Compositions also contain oils and modified oils like soyabean oil, com oil, rice bran oil,
arachis oil, sunflower oil, sesame oil, peppermint oil, lime oil, ethyl oleate, benzyl
benzoate, ethyl linoleate, triacetin, ethyl laurate, propylene glycol monocaprylate
(Capryol 90™, Capryol PGMC™, Sefsol 218™), Polyethyleneglycol 6-esters (Labrafil
1944 CS), isopropyl myristate, oleic acid, medium chain triglycerides, capric-capryiic,
lauric or oleic mono, di and tri glycerides marketed under trade name of Labrafils,
Labrafacs, Lauroglycols, Plurols, Akoline, Akomed, Akonons, Myvacets, Captex and
Capmul either alone or in combination.
The present investigation is more specifically explained by following examples.
However, it should be understood that that.the scope of the present invention is not
limited by the examples in any manner. It will be appreciated by any person skilled in this
art that the present investigation includes the following examples and further can be
modified and altered within the technical concept of the present investigation.
8

EXAMPLES
Example 1:
SolutolHS 15 12-20 gms.
Propofol 1 gm.
Sterile Water for injection (SWFI) or 0.9% saline q.s. 100 gms.
Example 2:
SolutolHS 15 8-12gm
Polysorbate 80 1-5gm
Propofol 1 gm.
SWFI or 0.9% saline q.s. 1oo gms.
Example 3:
Solutol HS 15 8-12gm
Propylene glycol 1-5gm
Propofol 1 gm.
SWFI or 0.9% saline q.s. 100 gms.
Example 4:
Solutol HS 15 8-12gm
Glycofurol 1-5gm
Propofol 1 gm.
SWFI or 0.9% saline q.s. 100 gms.
Example 5:
SolutolHS 15 8-12gm
EihanoJ 1-5gm
Propofol 1-gm
SWFI or 0.9% saline q.s. 100 gms.
9

Example 6:
SolutolHS 15 4-12gm
BL9EX l-5gm
Propofol 1 gm.
SWFI or 0.9% saline q.s. 100 gms.
Example 7:
BL9EX 7-15gm
Propofol 1 gm.
SWFI or 0.9% saline q.s. 100 gms.
Example 8:
Solutol HS 15 8-12gm
Labrasol l-4gm
Propofol 1 gm.
SWFI or 0.9% saline q.s. 100 gms.
Example 9:
SolutolHS 15 8-12gm
Lecinol SHE 50 1-5 gms
Propofol 1 gm.
SWFI or 0.9% saline q.s. 100 gms.
The compositions described in the aforementioned examples can be prepared by mixing
all the ingredients except aqueous phase (SWFI or 0.9% saline) with the help of gentle
heat (60°C) to effect a homogenous solution. These compositions can be stored as
preconcentrate in a suitable glass vial and can be diluted with SWFI or 0.9%saline
whenever required to yield Propofol (l%w/w) in solubilized form. The compositions can
also be diluted with other vehicles such as 2.25% glycerol, 5% dextrose and 5% sorbitol.
10

Example 10:
Lecinol SHE 50 8-15gm
BL9EX 5-10gm
Triclosan 1gm
Capryol90 l-4gm
Distilled Water q.s. 1 OOgm
Triclosan is first dissolved in Capryol 90 with the help of magnetic stirring. TO this oily
solution Lecinol SHE 50 and BLEX are added. This preconcentrate after dilution with
water or buffer spontaneously yields microemulsion with globule size less than 200nm.
Example 11:
Cremophore EL 0.1-0.4gm
Capryol 90 0.2-0.4gm
Cefpodoxime proxetil 0.13gm
Example 12:
Solutol HS 15 0.2-0.4gm
Capmul MCM C-8 0.1-0.4gm
Cefpodoxime proxetil 0.13gm
Example 13:
Polysorbate 20 0.2-0.4gm
Labrafil 1944 CS 0.05-0.15gm
Capryol 90 0.1-0.4gm
Cefpodoxime proxetil 0.13gm
Example 14:
PoloxamerlSS 0.2-0.4gm
Capryol 90 0.1-0.4gm
Cefpodoxime proxetil 0.13gm
11

Example 15:
Poloxamer 407 0.2-0.4gm
Capryol 90 0.1-0.4gm
Cefpodoxime proxeti 1 0.13 gm
Example 16:
Cremophore EL 0.2-0.4gm
Akoline MCM 0.05-0.15gm
Capryol 90 0.1-0.4gm
Cefpodoxime proxetil 0.13gm
Example 17:
Cremophore EL 0.2-0.4gm
Gelucire 44/14 0.05-0.15gm
Capryol 90 0.1-0.4gm
Cefpodoxime proxetil 0.13gm
The compositions described in the examples 11 to 17 can be prepared by first dissolving
Cefpodoxime proxetil in oily phase with the help of magnetic stirring and then by adding
the remaining ingredient followed by gentle heating at 60°C (whenever required) to yield
a homogenous preconcentrate. These preconcentrates would yield microemulsions or
nanoemulsions after dilution with distilled water or physiological buffers. These
preconcentrates can be filled in hard gelatin or soft gelatin capsules or can be adsorbed
onto solid carriers to obtain a unit dosage form. These compositions after ingestion would
present Cefpodoxime proxetil in nanoemulsified form in vivo.
Various experiments performed with some selected compositions would be presented
herein. In all the experiments related to Propofol, compositions described in Examples 2,3
and 4 are used. In all the experiments related cefpodoxime proxetil, composition
described in Example 16 is used.
12

Experiment 1
Globule size of Propofol:
The compositions described in Examples 2,3 and 4 were diluted suitably with 0.9% saline
and the globule size of Propofol was determined by using photon correlation spectroscopy
(PCS). The globule size of Propofol was found to be less than 30nm in all the cases.
Moreover, there was no considerable increase in the globule size on storing the
microemulsions for 18 hrs confirming their suitability for IV infusion of Propofol.
Experiment 2:
pH determination:
The compositions described in Examples 2,3 and 4 were prepared and their pH was
determined in triplicate at room temperature. The compositions exhibited pH in the range
of 4.7-5.1
Experiment 3:
Effect of centrifugation and freeze-thaw cycling:
The compositions described in Examples 2,3 and 4 were prepared. The compositions
were centrifuged at 5000 rpm for 20 min to assess effect of centrifugation. Furthermore,
compositions were subjected to freeze-thaw cycling. One freeze-thaw cycle consisted of
storing of compositions at -20°C for 24 h. After this, they were stored at room
temperature for another 24 hrs. Compositions could withstand centrifugation and freeze-
thaw cycling.
Experiment 4:
Effect of autoclaving;
The preconcentrates described in Examples 2,3 and 4 were prepared, filled in glass vials,
sealed and sterilized by autoclaving at 121°C for 15 min. The effect of autoclaving was
f
determined by evaluating the Propofol content, globule size and pH of the compositions
before and after the autoclaving.
Autoclaving did not have any significant effect on the Propofol content, globule size and
pH of the compositions.
13

Experiments:
In vitro hemolysis:
In vitro hemolysis of compositions described in Examples 2, 3 and 4 was assessed using
heparinized fresh human whole blood. Blood samples were pooled and subdivided into
three portions (1.6 ml each) and each of the portions Was spiked with various Propofol
microemulsions (0.4 ml) such that the final concentration of Propofol in all the blood
samples was 10 ng/ml.
Immediately after addition, the blood-microemulsion mixture was gently agitated for
5-10 seconds and incubated at 37°C for 2 hrs. After incubation, the mixtures were placed
in the ice-cold water for 2 min to quench the hemolytic process. The intact red blood cells
were separated from the supernatant by centrifugation at 3000 rpm for 5 min at 5°C. The
negative control was prepared by incubating 1.6 ml of blood with 0.4 ml of 0.9 % sodium
chloride solution at 37°C for 2 h. In order to obtain I00°/0 hemolysis of the blood, 1.6 ml
of blood was diluted with 14.4 ml of double distilled water and the mixture was incubated
at 37°C for 30min. This sample served as positive control. The controls received same
treatment as that of test samples so as to separate intact erythrocytes from the mixture.
However, in case of negative control all the erythrocytes remained intact and in case of
positive control none of the erythrocytes remained intact.
The supernatant from all the samples (including positive and negative control) was
removed, transferred to another microcentrifuge tube and centrifuged again at 3000 rpm
for 5 min at 5°C in order to get rid of any intact erythrocytes that may have come while
withdrawing the supernatant. Supernatant, 0.3 ml was Suitably diluted with 4.15 ml of
0.9% saline in case of test samples and negative control and with double distilled water in
case of positive control and analyzed for the content of hemoglobin by measuring the
absorbance of supernatant at 540 nm.
The extent of hemolysis as percentage (% H) was determined by using following equation
% H = [(Abs - Abs control) / (Abs100 - Abs control)X 100
where,
Abs is absorbance of sample,
Abs control is absorbance of control sample (negative control),
Absioo is absorbance of sample in which 100 % hemolysisj occurred (positive control).
14

The compositions led to very negligible hemolysis (less than 1%) even after 2 hrs of
contact with blood.
Experiment 6:
In-vivo anesthetic efficacy
In-vivo anesthetic efficacy was carried out to test anesthetic power of the developed
Propofol formulations. The efficacy of developed formulations was compared with
marketed Propofol emulsion (Propovan™, Bharat Serums Pvt Ltd., Mumbai).
Adult female Wistar rats with body mass of 200-250 g, were obtained from Hafflcins
Institute, Mumbai at the beginning of the experiments. Rats were maintained under an
artificial 12 h light-dark cycle (lights on from 08:00 to 20:00 h) and at a constant
temperature of 23 ± 2°C and 65% humidity. Food and water were freely available, and the
animals were acclimatized for >7 days before use. Experiments were performed between
08:00 and 14:00 h. Animal care and handling throughout the experimental procedure
were performed in accordance to the CPCSEA guidelines. The experimental protocol was
approved by the Animal Ethical Committee of the Bombay College of Pharmacy. Rats
were injected intravenously (single bolus in the lateral tail vein) with the different
formulations of Propofol, each containing equimolar concentration of Propofol [10
mg/(ml kg)]. For intravenous administration, animals were restrained in an appropriate
plexiglass cage and a tail vein was used. Following the drug administration, rats (six per
treatment group) were observed for the following 60 min, and the onset and duration of
loss of the righting reflex (LORR) were recorded. The duration of LORR, expressed as
mean ± S.D. was subjected to statistical analysis. The statistical significance of
differences in the duration of LORR data were analyzed utilizing analysis of variance
(ANOVA) followed by Dunnet's test (GraphPad InStat Demo Version). Differences were
considered statistically significant at P 15

The results of the in vivo anesthetic efficacy test are shown below in table 1
Table 1: Comparison of developed Propofol formulation with marketed formulation

Duration of LORR (minutes)
Animal Propovan™ Example 2 Example 3 Example 4
1 10.57 13.42 13.02 13.48
2 13.22 11.59 13.07 14.24
3 10.41 15.25 15.37 14.17
4 11.21 15.38 15.1 12.08
5 15.05 12.42 17.49 15.38
6 17.05 16.45 18.1 18.1
12.918 ±2.699 14.085 ± 1.9 15 .358 ± 2.136 14.575 ±2.038
Experiment 7:
Globule size analysis of cefpodoxime proxetil preconcentrate:
Composition described in example 15, 50 mg was diluted to 50 ml with different dilution
media viz. double distilled water, buffer pH 1.2, buffer pH 3.0 and pH 6.8 buffer. The
mean globule size and size distribution of resulting nanoemulsions was determined using
PCS.
The globule size of all the nanoemulsions was found to be less than 200nm.
The compositions in this investigation can be utilized for the parenteral, peroral, topical
delivery of the hydrophobic agents belonging to the therapeutic classes like
immunosupressants, anti-viral agents, vitamins, anti-adrenergic agents, adrenergic agents,
cholinergic agents, anti-cholinergic agents, anti-migrane agents, anti-parkinsonian agents,
anti-alzhimer agents, anti-acne agents, anti-glaucoma agents, steroidal agents, anti-
arthritic agents, anti-bacterial agents, anti-malarial agents, anti-parasitic agents, anti-
cancer agents, anti-inflammatory agents, diuretic agents, hypoglycemic agents, anti-
hyperlipidemic agents, anti-hypertensive agents, anti-fungal agents, anti-histaminics, anti-
protozoal agents and others categories comprising of hydrophobic agents.
16

It will be evident to those skilled in the art that the invention is not limited to the details
of the foregoing illustrative examples and that the present invention may be embodied in
other specific forms without departing from the essential attributes thereof, and it is
therefore desired that the present embodiments and examples be considered in all respects
as illustrative and not restrictive, reference being made to the appended claims, rather
than to the foregoing description, and all changes which come within the meaning and
range of equivalency of the claims are therefore intended to be embraced therein.
17

I claim,
1. Pharmaceutical preconcentrate compositions comprising one of the hydrophobic
pharmaceutical components, Propofol, Cefpodoxime proxetil and Triclosan as an
active ingredient with suitable pharmaceutically acceptable excipients selected
from the group consisting of surfactants, co-surfactants, solubilizers, oils or
modified oils and stabilizers either alone or in combination.
2. Pharmaceutical preconcentrate compositions of claim 1, wherein Propofol
compositions upon dilution with sterile water or 0.9% saline yields solution of
Propofol with concentration of l%w/w.
3. Pharmaceutical preconcentrate compositions of Propofol as claimed in claim 1
and claim 2, wherein at least one of the surfactant is selected from the group
consisting of polyethylene glycol-15-hydroxystearate (Solutol HS 15), BL9EX,
Polyoxyethylene sorbitan esters like Polysorbate 80, Poloxamers like poloxamer
407, Polyoxyethylene alkyl ethers like Brij 58, Lecithis and modified lecithins like
Lecinol SHE 50™, Capryl-caproyI macrogol-8 glyceride (Labrasol™) either
alone or in combination with with solubilizers and co-surfactants
4. Pharmaceutical preconcentrate compositions of Propofol as claimed in claim 1 and
claim 2, wherein at least one of the co-surfactant or solubilizer is selected from the
group consisting of ethanol, propylene glycol, glycofurol, glycerol and
polyethylene glycol.
5. Pharmaceutical preconcentrate compositions of Propofol as claimed in claim 1 to
claim 4, wherein the preconcentrate compositions are prepared by mixing
Propofol and surfactant and/or co-surfactant or solubilizer by gentle heating at
60°C to obtain a homogeneous mixture which upon dilution with sterile water or
0.9% saline yield Propofol (l%w/w) in solubilized form with globule size less
than 200nm having pH in the range of 4.7 to 5.1.
18

6. Pharmaceutical preconcentrate compositions of claim 1, wherein the hydrophobic
pharmaceutical component is Cefpodoxime proxetil and the compositions are
prepared by dissolving Cefpodoxime proxetil in oily phase using magnetic stirrer
and addition of the surfactants and/or co-surfactants by gentle heating at 60°C to
yield a homogeneous preconcentrate in a self nanoemulsified form upon dilution
with distilled water or physiological buffer, with globule size less than 200nm
7. Pharmaceutical preconcentrate compositions of Cefpodoxime proxetil as claimed
in claim 1 and claim 6, wherein at least one of the surfactant is selected from the
group consisting of Polyethylene glycol-15-hydroxystearate (Solutol HS 15),
BL9EX, Polyoxyethylene sorbitan esters like Polysorbate 80, Poloxamers like
poloxamer 407, Polyoxyethylene alkyl ethers like Brij 58, Lecithis and modified
lecithins (Lecinol SHE 50™), Capryl-caproyl macrogoI-8 glyceride (Labrasol™),
Castor oil based surfactants such as Polyoxyl 35 Castor Oil (Cremophore EL) and
Polyoxyl 40 Hydrogenated Castor Oil (Cremophore RH 40) either alone or in
combination with other ingredients.
8. Pharmaceutical preconcentrate compositions of Cefpodoxime proxetil as claimed
in claim 1 and claim 6, wherein at least one of the co-surfactant or solubilizer is
selected from the group consisting of ethanol, propylene glycol, tetrahydrofurfuryl
alcohol polyethylene glycol ether (glycofurol or tetraglycol), glycerol,
polyethylene glycol, diethylene glycol monothyl ether (Transcutol™) and medium
chain mono-, di-, triglycerides like Akoline, Sefsof, Akonons, Myvacets and
Capmuls like Caprylic/Capric Glycerides (Akoline MCM), Medium Chain Mono-
& Djglycerides (Capmul MCM) and Glyceryl Monocaprylate (Capmul MCM-
C8).
9. Pharmaceutical preconcentrate compositions of Cefpodoxime proxetil as claimed
in claim 1 and claim 6, wherein at least one of the oils is selected from the group
consisting of soyabean oil, corn oil, rice bran oil, arachis oil, sunflower oil,
sesame oil, peppermint oil, lime oil, ethyl oleate, benzyl benzoate, ethyl linoleate,
triacetin, ethyl laurate, propylene glycol monocaprylate (Capryol 90™, Capryol
19

PGMC™), Sefsol 218™), Polyethyleneglycol 6-esters (Labrafil 1944 CS),
isopropyl myristate, oleic acid, medium chain triglycerldes, capric-caprylic, lauric
or oleic mono, di and tri glycerides like Labrafils, Labrafacs, Lauroglycols,
Plurals, Akoline, Akomed, Akonons, Myvacets, Captex and Capmul either alone
or in combination.
10. Pharmaceutical preconcentrate compositions of claim 1, wherein the hydrophobic
pharmaceutical component is Triclosan l%w/w and the compositions are prepared
by dissolving Triclosan in modified oil by magnetic stirring and addition of one or
more surfactants to this oily mixture which upon dilution with water or buffers
yields microemulsified form with globule size less than 200nm,
11. Pharmaceutical preconcentrate compositions of Triclosan as claimed in claim 1
and claim 10, wherein at least one of the surfactant is selected from the group
consisting of Polyethylene glycol-15-hydroxystearate (Solutol HS 15), BL9EX,
Polyoxyethylene sorbitan esters like Polysorbate 80, Poloxamers like poloxamer
407, Polyoxyethylene aJkyl ethers like Brij 58, Lecithis and modified lecithins
(Lecinol SHE 50™), Capryl-caproyl macrogol-8 glyceride (Labrasol™), Castor
oil based surfactants such as Polyoxyl 35 Castor Oil (Cremophore EL) and
Polyoxyl 40 Hydrogenated Castor Oil (Cremophore RH 40) either alone or in
combination with other ingredients.
12. Pharmaceutical preconcentrate compositions of Triclosan as claimed in claim 1
and claim 10, wherein at least one of the co-surfactant or solubilizer is selected
from the group consisting of ethanol, propylene glycol, glycofurol, glycerol,
polyethylene glycol, diethylene glycol monothyl ether (Transcutol™) and medium
chain mono-, di-, triglycerides like Akoline, Sefsol, Akonons, Myvacets and
Capmuls like Caprylic/Capric Glycerides {Akoline MCM), Medium Chain Mono-
& Diglycerides (Capmul MCM) and Glyceryl Monocaprylate (Capmul MCM-
C8).
13. Pharmaceutical preconcentrate compositions of Triclosan as claimed in claim 1
and claim 10, wherein at least one of the oils is selected from the group consisting
20

of soyabean oil, corn oil, rice bran oil, arachis oil, sunflower oil, sesame oil,
peppermint oil, lime oil, ethyl oleate, benzyl benzoate, ethyl linoleate, triacetin,
ethyl laurate, propylene glycol monocaprylate (Capryol 90™), Sefsol 218™),
Polyethyleneglycol 6-esters (Labrafil 1944 CS), isopropyl myristate, oleic acid,
medium chain triglycerides, capric-caprylic, lauric or oleic mono, di and tri
glycerides like polyoxyethylenated vegetable oils (Labrafils), Labrafacs,
Laurogfycols, Plurols, Akoline, caprylic/capric triglyceride(Akomed), Akonons,
Acetylated monoglycerides (Myvacets), Captex and Capmul either alone or in
combination.
14. Pharmaceutical preconcentrate compositions as claimed in any of the preceding
claims 1 to 13, their process of preparation and evaluation as described herein
with reference to the foregoing examples 1-17.
21
Dated this 25th day of May 2006

Documents:

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Patent Number

269000

Indian Patent Application Number

742/MUM/2005

PG Journal Number

40/2015

Publication Date

02-Oct-2015

Grant Date

28-Sep-2015

Date of Filing

22-Jun-2005

Name of Patentee

NAGARSENKER MANGAL SHAILESH

Applicant Address

A-401, VIKAS PALMS,AMBEDKAR ROAD,THANE (WEST)- 400 602,

Inventors:

#	Inventor's Name	Inventor's Address
1	NAGARSENKAR MANGAL SHAILESH	A-401, VIKAS PALMS, AMBEDKAR ROAD, THANE (WEST)- 400602
2	DATE ABHIJIT ASHOK	DATAR BULIDING, PATEL ROAD, NEAR JOSHI HIGH SCHOOL, SARASWAT COLONY, DOMBIVLI (E)-421201

PCT International Classification Number

C07D501/60

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA