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WO2013008083A1 - Composition pharmaceutique pouvant améliorer l'efficacité anticancéreuse du tamoxifène - Google Patents

Composition pharmaceutique pouvant améliorer l'efficacité anticancéreuse du tamoxifène Download PDF

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Publication number
WO2013008083A1
WO2013008083A1 PCT/IB2012/001361 IB2012001361W WO2013008083A1 WO 2013008083 A1 WO2013008083 A1 WO 2013008083A1 IB 2012001361 W IB2012001361 W IB 2012001361W WO 2013008083 A1 WO2013008083 A1 WO 2013008083A1
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Prior art keywords
tmx
pharmaceutical composition
surfactant
snedds
tamoxifen
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Inventor
Sanyog JAIN
Omesh Mallappa BHUSHINGE
Amit Kumar Jain
Nitin Kumar SWARNAKAR
Harshad Prakash HARDE
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National Institute of Pharmaceutical Education and Research
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National Institute of Pharmaceutical Education and Research
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine

Definitions

  • the present invention relates to the field of drug delivery systems. More specifically, it relates to a novel pharmaceutical composition for enhancing the anticancer efficacy of Tamoxifen in the form of a self-nanoemulsifying delivery system (SNEDDS).
  • SNEDDS self-nanoemulsifying delivery system
  • Tamoxifen is a non-steroidal triphenylethylene derivative and is the first selective estrogen receptor modulator (SERM). It is a drug of choice for the treatment of advanced stage of breast cancer and has been approved by the US Food and Drug Administration (FDA) in late 1998. Therapeutic effect of Tmx is due to its interaction with breast cancer cells which possesses estrogen receptors (ER) vis-a-vis competition with natural estrogen to bind with estrogen receptor in breast cancer cells.
  • SERM selective estrogen receptor modulator
  • Tmx is prescribed as Tmx citrate tablets and oral solution (10-20 mg/day) for 3-5 years as the chronic therapeutic regimen.
  • the salt form of the Tmx overcomes its poor aqueous solubility, Tmx citrate is precipitated in the gastric environment after oral administration, which limits its oral bioavailability.
  • the oral bioavailability of Tmx also suffers due to extensive first pass metabolism which causes drug induced hepatotoxicity. Further, poor oral bioavailability results in its reduced concentration in the tumor vicinity.
  • Tmx has been formulated in nanospheres of poly-e-caprolactone, long circulating PEG coated nanoparticles, Tmx loaded ⁇ -cyclodextrin nanoparticles, and solid lipid nanoparticles.
  • These approaches involved intravenous route of administration to attain required amount of drug at tumor site for certain period of time and minimizing side effects on other body organs and not an oral route of administration.
  • Efforts were also made by co-administration of Tmx with cytochrome P-450 family (CYP3A) and P- glycoprotein inhibitors (P-gp) inhibitors like, epigallocatechin gallate (EGCG) and naringin to increase its oral bioavailability.
  • CYP3A cytochrome P-450 family
  • P-gp P- glycoprotein inhibitors
  • EGCG epigallocatechin gallate
  • naringin solid lipid nanoparticles.
  • Tmx formulations which can provide a more efficient means of administering Tmx with improved bioavailability, without causing undesired side effects. Also, a formulation with improved stability and hence longer shelf life is desirable.
  • the present invention has thus gone against the present views and developed a composition using base form of the drug and surprisingly, the present compositions show improved bioavailability, anticancer efficacy and reduced toxicity when compared with the Tmx citrate salts and Tmx citrate SNEDDS.
  • the object of the present invention to develop a pharmaceutical composition of Tmx in self-nanoemulsifying drug delivery systems (SNEDDS) for enhancing its anticancer efficacy.
  • the composition has high oral bioavailability, reduced ⁇ toxicity and more stability as compared to the prior art formulations.
  • specific oily phase and specific surfactant and co surfactant mixture aids in developing an optimum and stable SNEDDS formulation for Tmx.
  • the object of the present invention is to develop a pharmaceutical composition of Tmx in a self nanoemulsifying drug delivery system (SNEDDS) with enhanced oral bioavailability, augmented anticancer efficacy and reduced toxicity for effective treatment of breast cancer.
  • a further object is to develop a stable SNEDDS formulation of Tmx using specific oily phases and specific surfactant/co-surfactant combinations.
  • the present invention discloses a pharmaceutical composition of Tmx in a self- nanoemulsifying drug delivery systems (SNEDDS) for enhancing its anticancer efficacy. Further, the compositions have high oral bioavailability, reduced toxicity and higher stability when compared with the prior art formulations.
  • Capmul MCM was selected as the oily phase on the basis of optimum solubility of Tmx in oil. Cremophor EL and ethanol were selected as surfactant and co-surfactants from a large pool of excipients, depending upon their nanoemulsifying ability for oily phase Capmul MCM.
  • Pseudoternary phase diagrams were constructed to identify the efficient self- nanoemulsification region in different dilution media viz., water, buffer pH 1.2 and buffer pH 6.8.
  • Optimized formulation, containing Cremophor EL-Ethanol- Capmul MCM: Tmx (40: 1 w/w) in the ratio of 30: 10:60 were selected based on its ability to form nanoemulsion in simulated gastric and intestinal fluid. The formulation was found to be robust when tested for its long-term room temperature stability of three months and short-term excursion of freeze thaw cycles.
  • the SNEDDS formulations of the present invention demonstrated 3.75 times enhancement in oral bioavailability as compared to Tmx citrate solution and 8.97 times as compared to Tmx base solution. Moreover, the SNEDDS formulation showed the improved anticancer efficacy and reduced hepatotoxicity when tested in DMBA (7, 12- dimethyl[a]benzanthracene) induced breast tumor model when compared to the SNEDDS (Tmx citrate) formulations and commercially available Tmx citrate. DESCRIPTION OF FIGURES
  • Fig. 4. illustrates the ternary Diagram of Tween 80-Carbitol-Capmul MCM composition.
  • Fig.5. illustrates the ternary diagram of Cremophore-EL-Ethanol-Capmul MCM.
  • Fig.6. illustrates the pseudo-ternary diagram of Tween 80-Carbitol-Capmul MCM: Tmx (15: 1 w/w Oil: drug).
  • Fig.7 illustrates the pseudo-ternary diagram of Cremophore-EL-Ethanol-Capmul MCM:Tmx (15: 1 w/w Oil: drug).
  • Fig.8. illustrates the pseudo-ternary diagram of Cremophor EL-Ethanol-Capmul MCM:Tmx (15: 1 w/w Oil: drug) in buffer pH 1.2.
  • Fig.9. illustrates the pseudo-ternary diagram of Cremophor EL-Ethanol-Capmul MCM:Tmx (15: 1 w/w Oil: drug) in buffer pH 6.8.
  • Fig.10 illustrates the pseudo-ternary diagram of Cremophor EL-Ethanol-Capmul MCM:Tmx (30: 1 w/w Oil: drug) in buffer pH 1.2.
  • Fig.11. illustrates the pseudo-ternary diagram of Cremophor EL-Ethanol-Capmul MCM:Tmx (30: 1 w/w Oil: drug) in buffer pH 6.8.
  • Fig.12. illustrates the pseudo-ternary diagram of Cremophor EL-Ethanol-Capmul MCM:Tmx (40: 1 w/w Oil: drug) in buffer pH 1.2.
  • Fig.13 illustrates the pseudo-ternary diagram of Cremophor EL-Ethanol-Capmul MCM:Tmx (40: 1 w/w Oil: drug) In buffer pH 6.8
  • AST aspartate transaminase (figure 16a)
  • ALT Alanine transaminase (figure 16b)
  • MDA malondialdehyde (figure 16c)
  • a Vs control b Vs Tmx citrate; * p ⁇ 0.05; *** p ⁇ 0.001
  • the present invention provides a novel pharmaceutical composition of Tmx in a SNEDDS for enhancing its anticancer efficacy.
  • the composition has high oral bioavailability, reduced toxicity and high stability.
  • the novel composition is in the form of anhydrous SNEDDS; which when comes in contact with the biological fluids, forms a nanoemulsion with a droplet size of less than 200 nm.
  • One aspect of the present invention provides a formulation of Tmx in the form of a SNEDDS wherein Tmx is in the form of a free base.
  • Yet another aspect of the invention provides a formulation of Tmx in the form of anhydrous SNEDDS which increases the oral bioavailability of Tmx when compared to the free Tmx base, commercially available Tmx-citrate tablets and Tmx citrate SNEDDS.
  • Tmx in the form of a self nanoemulsifying drug delivery system which enhances the anticancer efficacy of Tmx when compared to the free Tmx base, commercially available Tmx-citrate tablets and Tmx citrate SNEDDS.
  • the present invention provides an anhydrous pharmaceutical composition of Tmx comprising the drug, oily phase, a surfactant and a co-surfactant.
  • the oily phase is selected from the group consisting of Isopropyl myristate (Loba Chemie, Mumbai), olive oil (Marico Ind. Ltd.), sunflower oil (Marico Ind. Ltd.), soyabean oil (Marico Ind. Ltd.), safflower oil (Marico Ind. Ltd.), coconut oil (Marico Ind.
  • Capmul MCM Glyceryl Mono- & dicaprate
  • Captex 355" Abitech Corp, Janesville
  • Capmul MCM C8 Glyceryl Monocaprylate
  • the surfactant is selected from group consisting of Tween 80, polyethoxylated castor oil (hereinafter “Cremophor EL”), Tween 20, Pluronic F 68, Gelucire, and combinations thereof.
  • the co-surfactant is selected from group consisting of Oleoyl macrogol-6 glycerides or Oleoyl polyoxyl-6 glycerides (hereinafter “Labrafil 1944 CS", Polyglyceryl-3 dioleate NF (hereinafter “Plurol Oleique CC 497”), ethanol, PEG 200, carbitol, ethylene glycol and combinations thereof.
  • One aspect of the present invention is to provide formulation, characterization, in vitro release studies, stability studies, oral pharmacokinetics, anticancer efficacy, and toxicity studies of the said compositions.
  • One or more embodiments of the present invention provides a process of manufacturing a pharmaceutical composition comprising Tmx in the oily SNEDDS, wherein the oily phase was selected based on the maximum saturation solubility of Tmx in a particular oil. Selected oily phase (0.3 g) was further mixed with different surfactants (0.3 g) followed by vortexing for 2-5 min and warming at 40-45°C for 30 seconds to form homogeneous isotropic mixture.
  • the isotropic mixture 50 mg was precisely weighed and diluted with double distilled water to 50 ml to yield fine emulsion.
  • the ease of formation of emulsions was monitored by noting the number of volumetric flask inversions required to give uniform emulsion.
  • the resulting emulsions were observed visually for the relative turbidity.
  • the emulsions were allowed to stand for 2 h and their transmittance was assessed at 638 nm by UV double beam spectrophotometer (Specord 200, Analytikjena, Germany) using double distilled water as blank. Then, the droplet sizes of the emulsions were determined by Zeta Sizer at 25"C (Malvern, UK).
  • the selected surfactants (0.2 g) were mixed with different co-surfactants (O. lg) and finally mixed with Oily phase (0.3 g) followed by vortexing for 2-5 min and warming at 40- 45"C for 30 seconds to form homogeneous isotropic mixture.
  • the isotropic mixture 50 mg, was precisely weighed and diluted with double distilled water to 50 ml to yield fine emulsion.
  • the size of the formed emulsion was again determined by Zeta Sizer at 25"C (Malvern, UK).
  • compositions with varying compositions of surfactant, co-surfactant and oil were prepared.
  • the surfactant concentration was varied from 10 to 70% (w/w)
  • oil concentration was varied from 30 to 90%
  • co-surfactant concentration was varied from 0 to 30% (w/w).
  • the various combinations of oil, surfactants and co-surfactants were formulated keeping the total composition 100%.
  • Compositions were evaluated for nanoemulsion formation by diluting 50 mg of each of the 70 mixtures to 50 ml with double distilled water. Globule size of the resulting emulsion was determined by Zeta Sizer at 25"C (Malvern, UK). Dispersions, having globule size 200 nm or below were considered acceptable.
  • the present invention provides a pharmaceutical composition wherein the oily phase, surfactant and co ⁇ surfactant is in the range of 30-90, 10-70 and 0-30 % w/w respectively.
  • Capmul MCM is selected as the oily phase
  • Cremophor EL is selected as the surfactant
  • Ethanol is selected as co- surfactant in the ratio of 60:30: 10 respectively for formulation of Tmx as SNEDDS.
  • the oily composition of the present invention comprises Tmx in the ratio of 40: 1 (w/w).
  • Tmx SNEDDS on dilution comprises globules having diameter of less than 200 nm.
  • the present compositions showed no sign of precipitation and phase separation in SGF, SIF, pH 1.2 and pH 6.8 and size remained ⁇ less than 200 nm in all the conditions.
  • compositions of the present invention are stable after storage at room temperature and 3 freeze-thaw cycles (freezing below 0°C for 24 hours followed by thawing at 40°C for 24 hours) with no change in globule size and self emulsification ability.
  • compositions of the present invention on single peroral administration of Tmx improves the bioavailability of Tmx in Sprague Dawley rats by 3.75 folds as compared to commercial formulation of Tmx (Tmx citrate) and 8.97 folds as compared to Tmx base.
  • compositions of the present invention suppressed the tumor growth by 76%, whereas the tumor growth was continuously increased up to 156% in marketed formulation of Tmx and approx. 562% in the control animals.
  • compositions of the present invention produce less oxidative stress on liver as both AST and ALT values, the biochemical markers of liver toxicity, were significantly low as compared to marked formulation of Tmx (Tmx citrate).
  • compositions of the present invention are employed for the effective management of breast cancer.
  • the compositions of the present invention have higher anticancer efficacy and lower toxicity when compared with the SNEDDS of Tmx citrate.
  • compositions of the present invention are synergistic compositions showing surprising properties.
  • the unexpected property observed in the present compositions which is not present in the individual ingredients is a controlled release of the Tmx from the delivery system.
  • the present invention provides a pharmaceutical composition in the form of a self-nanoemulsifying drug delivery system (SNEDDS) comprising Tamoxifen, Capmul MCM, Cremophor EL and Ethanol; wherein the ratio of Capmul MCM: Tamoxifen is in the range of 15: 1 to 40: l(w/w).
  • SNEDDS self-nanoemulsifying drug delivery system
  • the present invention provides that pharmaceutical composition can be used for treatment of cancers preferably breast cancers.
  • the present invention provides that pharmaceutical composition can be used for treatment of infertility, Gynecomastia, bipolar disorders, angiogenesis or riedel thyroiditis.
  • Example 1 The invention is illustrated by the following examples which are only meant to illustrate the invention and not act as limitations.
  • Example 1 The invention is illustrated by the following examples which are only meant to illustrate the invention and not act as limitations.
  • the present invention includes a novel composition for the formulation of an oily mixture containing Tmx which upon contact with the GIT fluids self emulsify to form the SNEDDS with the size ⁇ 200 nm.
  • Solubility of Tmx in various oil and surfactants was determined which gave the implication of the solubilizing capacity of oil and surfactants and maximum drug could be entrapped in the formulation [C.W. Pouton, 1997; Pouton et al., 2000].
  • Solubility of Tmx in various oils, surfactants and surfactant solutions (10% w/w) is presented in Fig. 1 , Fig. 2 and Fig. 3 respectively. As indicated from Fig.1.
  • Tmx has greater solubility in polar oils rather than triglycerides.
  • the higher solubility of Tmx in medium chain glycerides than long chain glycerides might be due to higher ester bond content per gram of the medium chain glycerides than long chain one. This also might be because of limited lipophilicity of Tmx though it is highly hydrophobic.
  • oleic acid solubilizes Tmx in the greatest amount (153.6 mg/g), as Tmx is weak base. But as it has been reported that oleic acid worsens the breast cancer [Pala et al., 2001], therefore it was not selected for further studies.
  • Capmul MCM (Glycerol monocaprylocaprate), being a polar oil, solubilizes Tmx in a considerable amount (about 101 mg/g) was thus selected for further study.
  • Capmul MCM contains about 60% monoacylglycerol, 35% diacylglycerol and 4% triacylglycerrol.
  • Tween 80 and Cremophor EL were selected as the surfactants for the solubilization of Tmx based on the solubility studies (Fig. 2) which could help in improving both solvent property and stability of SNEDDS formulation. As revealed from Fig. 3, surfactant solutions have poor solubilizing capability for Tmx thus indicate the poor micellar solubility of Tmx among the screened surfactants.
  • Pluronic F68 since failed in spontaneity to form nanoemulsion was not selected for further studies; though it formed nanoemulsion with nearly monodispersed droplets. Cremophor EL and Tween 80 formed very good nanoemulsions requiring short time for nanoemulsification and were selected for further investigation.
  • Plurol oleique CC 497 oleic acid backbone in structure
  • Labrafil 1944 CS Oleic and linoleic acid backbone in structure
  • Cremophor EL-Ethanol-Capmul MCM combination formed stable nanoemulsion at the lower concentration of Cremophor EL even at 15% w/w, with increase in the nanoemulsification ability. Conversely, at the higher cremophore-EL concentrations less spontaneous nanoemulsion was formed requiring more sheer suggesting the addition of co-surfactant during the formation of nanoemulsion (>40% w/w). The formations of a viscous liquid crystalline gel like structure at the interface of formulation and an aqueous fluid phase explains this concept.
  • Tween 80 (HLB>12) at the higher concentration loose its tight junction property upon dilution with the aqueous fluid phase which may lead to formation of some larger droplets along with smaller ones [Buyukozturk et al., 2009]; due to which Tween 80 based systems might have shown larger PDI as compared to Cremophore- EL based system.
  • Tmx When Tmx was added into the system containing the cremophore-EL, they formed the nanoemulsion with narrow PDI at the higher surfactant concentration as compared to the system without Tmx.
  • Tween 80 based SNEDDS formulation contains too much hydrophilic excipient at higher concentration range of either surfactant or co-surfactant and it may lose considerable amount of its nanoemulsion formation capacity on dispersion in water (Buyukozturk et a ., 2009).
  • the shrinkage of the nanoemulsification region in case of Tween 80- Carbitol-Capmul MCM: Tmx could be explained on this basis.
  • Tween 80-Carbitol-Capmul MCM composition All the components present in Tween 80-Carbitol-Capmul MCM composition have the high solvent capacity and can solubilize Tmx greater than the used amount. Moreover, some part of the Tmx precipitated during the dilution with the aqueous fluids phase so as to make the nanoemulsification narrower.
  • the mean globule size of the resulting dispersions was measured by using Zeta Sizer at 25"C and the data obtained was used to identify the area of nanoemulsion formation.
  • the phase diagrams showing effect of Tmx and pH of the aqueous phase on phase behavior and area of nanoemulsion formation are shown in Fig.8-Fig.13.
  • the area of nanoemulsion region increased.
  • Incorporation of Tmx in Capmul MCM led to a considerable reduction in the area of nanoemulsion formation of Cremophore based SNEDDS.
  • the area of nanoemulsion formation was largest at pH 1.2 as compared to pH 6.8.
  • Tmx due to its low aqueous solubility, is likely to participate in the nanoemulsion by orienting at the interface. The reduction in the area of nanoemulsion formation thus could be due to Tmx influenced interaction of surfactant and co-surfactant with oil.
  • Tmx at the ratio of 40: 1 w/w in the capmul MCM showed the lager nanoemulsification region as 40: 1 w/w ratio was selected as drug loading ratio for the further investigation in the present invention (Fig.12 and Fig.13).
  • SGF gastric fluid
  • SIF simulated intestinal fluid
  • selected formulations were evaluated for their stability and ability of nanoemulsion formation in SGF and SIF, with the aim of selecting optimized final formula of SNEDDS formulations.
  • SGF and SIF were prepared according to USP, XXVII.
  • 50 mg of selected Tmx loaded SNEDDS formulations were diluted with 50 ml of either SGF or SIF and evaluated for their nanoemulsion ability by zeta sizer by determining the droplet size.
  • the selection of optimized formula for the self nanoemulsifying drug delivery systems was dependent on various factors.
  • the optimized composition should not be at the extremity of the nanoemulsification region (in the ternary phase diagram) so as to maintain stability of the formed nanoemulsion at the changed temperature condition due to the presence of electrolytes and/or GIT enzymes [Gelebi et al., 2008], It is also important in case of SNEDDS to select formulations with low quantity of surfactant, within the limits of regulatory guidelines. Considering all these facts, only three formulations comprising oil, surfactant and co-surfactant in the weight ratio of 60:30: 10, 65:25: 10 and 60:25: 15 were evaluated for their stability and nanoemulsifying ability in SGF and SIF.
  • Nanoemulsions resulting from dilution of SNEDDS were found to be robust at all dilutions (Table 5) and did not show any sign of phase separation and precipitation except some opalescence at 200 times dilution.
  • the inventors found that the formulation showed extensive aggregation/precipitation in water and Hydrochloric acid after 48 hours.
  • Cremophor EL-Ethanol-Capmul MCM Tmx (40: 1) in the ratio of 30: 10:60.
  • the mean globule size of Tmx SNEDDS after dilution with various dissolution media is given in Table 6.
  • the time required for formation of nanoemulsions after dilution with various dissolution media was about 2-3 min.
  • the resulting nanoemulsions were almost transparent with some opalescence in appearance and they did not show any signs of phase separation and turbidity even after 6 h.
  • the zeta potential of SNEDDS when checked in double distilled water was found negative, -16.3 ( ⁇ 2.74) mV in absence of Tmx while the same was +9.5 ( ⁇ 3.12) mV in presence of Tmx. This might be due to participation of Tmx at the interface of droplets.
  • the viscosity of the SNEDDS formulation (0.5 g) was determined without dilution using a Brookfield DV III cone and plate rheometer (Brookfield Engineering Laboratories, Inc, USA) using spindle RV SC4-21 at 25 ⁇ 0.5"C.
  • the software used for the viscosity calculations was Rheocalc V2.6. Since developed SNEDDS formulations required to be filled into either soft or hard gelatin capsule as final dosage form, it was necessary to determine viscosity of SNEDDS as it ultimately determines the capsule filling process parameters. Viscosity affects the flow property of formulation and ultimately accuracy and time required for capsule filling procedure. Viscosity of developed SNEDDS formulation as determined using Brookfield, cone and plate rheometer was found to be 350.22 ( ⁇ 2.91) cP at 25"C.
  • Table 7 summarizes the results of stability samples.
  • the formulations were found to be stable for both 6 months of long-term room temperature conditions and short period excursions of freeze thaw cycles. There were no changes in the appearance, self-nanoemulsifying property and droplet size and droplet size distribution of the resultant emulsion. Furthermore, the formulation was found to show no phase separation or drug precipitation. In case of freeze thaw cycles also there were no changes in the parameters tested like that of room temperature stability (Table 7). Even the formulation did not get solidified upon freezing except some decrease in their flowability and it regained its original form when brought to room temperature with no signs of phase separation or drug precipitation. Thus, these studies confirmed the stability of the developed formulation for the tested conditions.
  • Freeze 1 1 1.16 ⁇ 3. 0.171 ⁇ 0.0 108.55 ⁇ 5. 0.203 ⁇ 0.0 109.55 ⁇ 4. 0.103 ⁇ 0.0
  • Tmx citrate salt solution, Tmx free base suspension and Tmx SNEDDS equivalent to Tmx base dose (10 mg/kg of body weight) were administered by oral gavages.
  • the blood samples (about 0.3 ml) were collected at 2, 4, 8, 12, 18, 24, 36, 48, 60h from the retro-orbital plexus under mild ether anesthesia into heparinized microcentrifuge tubes (containing 20 ⁇ 1 of 1000 IU heparin/ml of blood). After each sampling, 1 ml of dextrose-normal saline was administered to prevent changes in the central compartment volume and electrolytes. Plasma was separated by centrifuging the blood samples at 10000 rpm for 10 min at 15"C. All samples were then analyzed by validated HPLC method by using 100 ⁇ plasma.
  • Figure 14 presents the mean plasma Tmx concentration versus time profiles obtained following oral administration of the Tmx citrate suspension, Tmx (free base) suspension, SNEDDS (Tmx citrate) and developed SNEDDS formulations.
  • the corresponding mean pharmacokinetic parameters for all formulations are presented in Table 8.
  • the total plasma concentrations and plasma concentrations at all time points in case of SNEDDS were significantly higher as compared to both suspension formulations in both fasted state.
  • double peaks of maximum concentrations were observed when SNEDDS formulation was given, and this could be either due to transportation of drug through lymphatic and/or enterohepatic circulation.
  • But SNEDDS formulation is having the tendency to transport trough the lymphatics rather than the enterohepatic circulation.
  • lymphatic lymphatic drug transport often continues over time periods longer than typically observed for drug absorption via the portal vein. This is because assembly of lipoproteins, association of drug with the lipoproteins and subsequently transfer of these lipoproteins through thoracic duct (which is about 38-45 cm long and the main duct for return of lymph to blood) to systemic circulation takes longer time. Additionally lymph, flows very slowly compared to blood because of absence of pumping action of heart. Thus lymphatic transport in case of fasted state also can be the reason behind multiple peaks of plasma concentration apart from enterohepatic circulation. The exciting results obtained showed that Tmx absorption was enhanced significantly by employing SNEDDS.
  • Tmx from the SNEDDS resulted in 3.75 times enhancement in oral bioavailability as compared to Tmx-Citrate suspension and 8.97 times enhancement in oral bioavailability as compared to Tmx-base solution. This could be because that the increased dispersion of Tmx in the SNEDDS could overcome the barrier of solubility-limited absorption as mentioned earlier.
  • the spontaneously formed nanoemulsions will present the drug in a dissolved form, and the drug in the soluble form will significantly enhance absorption. Also effect of droplet size on mechanisms of drug absorption may improve the release and facilitate lymphatic transport [Bachynsky et al., 1997].
  • Tmx loaded SNEDDS formulations the droplet size range was reduced to less than 200 m, resulting in an increase in surface area for absorption. Additionally, in SNEDDS formulation especially that of the medium chain glycerides there is no further need of lipolysis for absorption to takes place [Tang et al., 2007]. Another property of developed Tmx loaded SNEDDS formulation is the zeta potential of nanoemulsion formed after dispersion into aqueous phase, which is positively charged. Many physiological studies have proved that the apical potential of absorptive cells, as well as that of all other cells in the body, is negatively charged with respect to the mucosal solution in the lumen.
  • the markedly decreased clearance value in SNEDDS in relation to suspensions might be explained by improved lymphatic transport pathway, reduced metabolism in the liver, and possible lipid protection of drug from enzymatic degradation.
  • Another advantage of SNEDDS formulations over conventional suspension or tablet is the lipid protection of Tmx from enzymatic degradation in intestine, thereby delaying and/or preventing intestinal first pass metabolism. It could therefore be concluded that the drug absorption into the systemic blood circulation and corresponding bioavailability were significantly enhanced by SNEDDS formulation. In case of Tmx citrate suspension, both Cmax and AUC were high as compared to free drugs.
  • Tmx citrate has adequate solubility (0.02% in 0.0 IN HC1) and has good permeability (BCS class II drug). This could also be revealed by the Tmax, which is 2h in performed pharmacokinetic study.
  • Tmx (free base) suspension had shown decreased Cmax and AUC. Tmx is practically insoluble in aqueous phase, but has good solubility in lipids. Thus the presence of lipids in food could have increased its solubility thus its absorption.
  • Tmx loaded formulation The assessment of in vivo antitumor efficacy after oral administration of Tmx loaded formulation was determined in DMBA (7, 12-dimethyl[a]benzanthracene) induced mammary carcinoma.
  • DMBA dimethyl[a]benzanthracene
  • the tumor developed animals were separated and randomly divided into three different treatment groups, namely control (no drug treatment), Tmx SNEDDS and Tmx citrate solution.
  • Tmx SNEDDS and Tmx citrate (equivalent to 3 mg/kg of Tmx) were administered to respective group animals every alternate day for a period of 35 days.
  • the tumor volume was measured on day first before treatment and thereafter every five days to check the antitumor efficacy of the formulations.
  • Formulations were administered at dose of 3 mg Tmx/kg body weight.
  • SNEDDS formulation suppressed the tumor growth significantly (pO.01) as compared to Tmx citrate.
  • the tumor growth was about 156% in case of Tmx citrate salt whereas the control group of animals showed the tumor growth upto the 562.19%.
  • the high antitumor activity of the SNEDDS formulation could be mainly due to lymphatic transport of Tmx. This is because; breast tumors are surrounded by auxiliary lymph nodes and a rich network of lymph vessels.
  • the ability of the present formulation to target the lymphatic system, thus bypassing the hepatic first pass effect could potentiates its antitumor activity.
  • the inherent capability of the present formulation to localize selectively in the lymphatic system improves its anticancer efficacy vis-a-vis reduce the side effect and toxicity. This could greatly reduce side effects and toxicities related to drugs.
  • FIG. 15 illustrates the efficacy of SNEDDS Tmx base over SNEDDS Tmx citrate formulations and commercially available Tmx citrate tablets.
  • the present compositions suppressed tumor growth by 76% whereas the tumor growth was about 156% in case of commercially available Tmx citrate.
  • the SNEDDS Tmx citrate showed tumor suppression comparable to the commercially available Tmx citrate.
  • Tmx citrate alanine aminotransferase
  • AST aspartate aminotransferase
  • Tmx SNEDDS 3 mg/kg
  • Tmx citrate suspension 3 mg/kg
  • the animals were treated every alternate day for 35 days.
  • 0.5 ml blood was collected from all animals under mild ether anesthesia and plasma was separated by centrifuging the blood samples at 10000 rpm for 10 min at 15"C.
  • Plasma concentrations of ALT and AST were then determined using commercially available kits by UV spectrophotometer.
  • SNEDDS formulation protects against Tmx induced hepatotoxicity and may be of therapeutic potential in alleviating the systemic side effects of Tmx therapy.
  • AST p ⁇ 0.05
  • ALT p ⁇ 0.001
  • MDA levels pO.001
  • SNEDDS formulation helps in transporting the most part of the drug through lymphatic system, while conventional suspension formulation has led the drug to travel through hepatic system which therefore increased the oxidative stress on liver. Once drug gets targeted to the lymphatic system it bypasses the hepatic metabolism of drug and therefore decreases the oxidative stress on liver.
  • Tmx citrate salt Tmx citrate

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Abstract

L'invention concerne une nouvelle composition pharmaceutique de tamoxifène pouvant améliorer son efficacité anti-cancéreuse pour une toxicité réduite. La composition se présente sous la forme d'un système d'administration de médicament auto-nanoémulsifiant (SNEDDS) comprenant, outre le tamoxifène, une phase huileuse, un tensioactif et un co-tensioactif.
PCT/IB2012/001361 2011-07-13 2012-07-11 Composition pharmaceutique pouvant améliorer l'efficacité anticancéreuse du tamoxifène Ceased WO2013008083A1 (fr)

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JP2019519602A (ja) * 2016-05-20 2019-07-11 アズール バイオテック, インコーポレーテッドAzure Biotech, Inc. 選択的エストロゲン受容体調節薬（ｓｅｒｍ）を含有する膣送達系およびその使用
EP3423033A4 (fr) * 2016-03-04 2020-01-01 Sharon Anavi-Goffer Compositions auto-émulsifiantes de modulateurs du récepteur cb2
US11458096B2 (en) 2014-04-09 2022-10-04 Pulse Pharmaceuticals Pvt. Ltd. Composition and method of producing nanoformulation of water insoluble bioactives in aqueous base

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11458096B2 (en) 2014-04-09 2022-10-04 Pulse Pharmaceuticals Pvt. Ltd. Composition and method of producing nanoformulation of water insoluble bioactives in aqueous base
EP3423033A4 (fr) * 2016-03-04 2020-01-01 Sharon Anavi-Goffer Compositions auto-émulsifiantes de modulateurs du récepteur cb2
JP2019519602A (ja) * 2016-05-20 2019-07-11 アズール バイオテック, インコーポレーテッドAzure Biotech, Inc. 選択的エストロゲン受容体調節薬（ｓｅｒｍ）を含有する膣送達系およびその使用
JP7168557B2 (ja) 2016-05-20 2022-11-09 アズール バイオテック，インコーポレーテッド 選択的エストロゲン受容体調節薬（ｓｅｒｍ）を含有する膣送達系およびその使用

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