* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Chapter-7 Summary
Survey
Document related concepts
Orphan drug wikipedia , lookup
Discovery and development of proton pump inhibitors wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Compounding wikipedia , lookup
Neuropharmacology wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Nicholas A. Peppas wikipedia , lookup
Theralizumab wikipedia , lookup
Pharmacognosy wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Prescription costs wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Drug discovery wikipedia , lookup
Drug interaction wikipedia , lookup
Transcript
Chapter 7 Summary CHAPTER-VII SUMMARY Acne is a common skin disorder afflicting more than 85% of adolescents and can persist or develop over time to affect up to 50% of adults older than 20 years of age. The largest population-based survey of acne involved 105 dermatology residents and just over 20,000 non institutionalized people in the USA. This study generated an overall US population acne prevalence estimate of 13%. Substantial healthcare resources and consumer expenditures are committed to the treatment of acne. In 2002, the total cost burden of acne and its treatment was estimated to exceed US$1 billion annually. Isotretinoin was approved in the United States in 1982 as a treatment for severe recalcitrant nodular (cystic) acne that is unresponsive to conventional therapy including systemic antibiotics. Isotretinoin is 13-cis retinoic acid or 13 cis-Vitamin A, its isomers and some of its analogs are widely known to leave a therapeutic activity in the treatment of several skin disorders like acne, hypertropic lupus erythmatosus, keratinization disorders. Some evidences also have been brought about the activity of Isotretinoin in basal cell carcinoma and squamous cell carcinoma. Isotretinoin decomposes in the presence of light and atmospheric oxygen. Isotretinoin is very poorly soluble in water what makes its bioavailability quite low after an oral intake of about 25% in fasted condition and 40% in fed conditions. The maximum concentration (Cmax) is reached after 2-4hrs, while the Cmax of the active metabolite, 4-oxo-isotretinoin is reached after 6hrs. The elimination half life of Isotretinoin is about 7 to 37 hrs while the half life t1/2 of Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 221 Chapter 7 Summary active metabolite is of 11 to 50 hrs. The steady state concentration is reached after 1 week of treatment. Very few publications and/or patents about the pharmaceutical formulation of Isotretinoin are available. The drug is available in most markets in the form of a soft gelatin capsule containing a fatty liquid formulation of Isotretinoin. The reported literatures show a maximum in-vitro drug release of about 60-70% even after 5 h. It is increasingly being recognized by the pharmaceutical industry that for these molecules, drug delivery systems play an important role for improving bioavailability. Although the process of passive diffusion is responsible for absorption of non ionized lipophilic molecules via the transcellular pathway, specialized absorption mechanisms, first pass metabolisms and efflux systems at the GI wall appear to play a major role for lack of absorption and poor bioavailability for some molecules. Nowadays, an increasing number of new chemical entities and many existing drugs exhibit low solubility in water, which may lead to poor oral absorption, high intra- and inter-subject variability and lack of dose proportionality. Thus, for such compounds of BCS II type, the absorption rate and degree from the gastrointestinal tract (GIT) are usually controlled and limited by dissolution process. To overcome the problem, various formulation strategies have been adopted including the use of cyclodextrins, nanoparticles, solid dispersions and permeation enhancers. In recent years, much attention has been paid to self-emulsifying drug delivery systems (SEDDS), which have shown lots of reasonable successes in improving oral bioavailability of poorly soluble drugs. SEDDS are usually Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 222 Chapter 7 Summary composed of a mixture of oil and surfactant or cosurfactant and are capable of forming fine oil-in-water emulsions upon gentle agitation provided by the GIT motion. After oral administration, SEDDS can maintain the poorly soluble drugs dissolved in the fine oil droplets when transiting through the GIT. Nanoemulsions have been reported to make the plasma concentration profiles and bioavailability of poorly soluble drugs more reproducible. Nanoemulsions have also been reported as one of the most promising techniques for enhancement of transdermal permeation and bioavailability of poorly soluble drugs. Nanoemulsions are thermodynamically stable transparent (translucent) dispersions of oil and water stabilized by an interfacial film of surfactant and cosurfactant molecules having a droplet size of less than 100 nm. Potential advantages of these systems include enhanced oral bioavailability (enabling dose reduction), more consistent temporal profiles of drug absorption, selective drug targeting toward a specific absorption window in the GI tract, and drug protection from the hostile environment in the gut. The concept of developing this novel formulation is derived from the burgeoning problems faced during the development of the bioequivalent generic formulation. The commercially available marketed product itself constituted batch to batch variability which further contributed to the variability caused by the nature of the molecule itself. This inadvertently created further hurdles in developing the generic version of Roacutane 20mg soft gelatin capsule product. This variation occurs mainly due to the particle size and solid state characteristics of Isotretinoin. The particle size of the active is mainly controlled by the API manufacturer during the recrystallization or purification step. The size reduction of the bigger particles causes serious blow in the purity and its physical characteristics due to the energy intensive milling process. Hence such process is mostly discouraged in the formulation industry but the quality of the product is Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 223 Chapter 7 Summary built through the input and in-process controls by controlling the API particle size in a narrow range at the vendor level itself. This makes the condition more complex and increases the cost of the active material and ultimately adds on the cost of the final formulation and makes the treatment expensive. The research work entitled "Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability " was undertaken with the following objective. The objective of this study was to develop and formulate a novel composition which shall be manufactured through easily scalable process at the formulation manufacturer site without involving sophisticated and energy intensive milling process irrespective of the particle size of the active material procured from the API manufacturer, to enhance the oral bioavailability of the Isotretinoin which will reduce the dose needed and decrease the risk of adverse side effects, to improve Tmax and reduce inter and intra subject variability and to address the stability issues associated with the Isotretinoin molecule. The study has been presented in 8 chapters with introduction in chapter 1, followed by literature review in chapter 2. The Drug and polymer profile was discussed in chapter 3. The objectives of the study were briefed in chapter 4 and elaborate methodology in chapter 5. Results and discussion was made in chapter 6. Summary was presented in chapter 7. Conclusion was finally presented in chapter 8 with up to date bibliography till 2010 related to the study at the end. The important criterion for selection of components is their pharmaceutical acceptability. It has been demonstrated that only very specific pharmaceutical excipient combinations lead to efficient nanoemulsion formulations. One important consideration when formulating a self emulsifying formulation is Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 224 Chapter 7 Summary avoiding precipitation of the drug on dilution in the gut lumen in-vivo. Therefore, the components used in the system should have high solubilization capacity for the drug, ensuring the solubilization of the drug in the resultant dispersion. Results from solubility studies reveal that Peppermint oil and Triacetin showed the highest solubilization capacity for Isotretinoin, followed by Polysorbate-80, Cremophore RH40, and Gelucire 44/14 among the surfactants and Transcutol HP, PEG 600 and Tetraglycol among the co-surfactants used. Self-nanoemulsifying systems form fine oil-water emulsions with only gentle agitation, upon their introduction into aqueous media. Surfactant and cosurfactant get preferentially adsorbed at the interface, reducing the interfacial energy as well as providing a mechanical barrier to coalescence. The decrease in the free energy required for the nanoemulsion formation consequently improves the thermodynamic stability of the nanoemulsion formulation. Therefore, the selection of oil and surfactant, and the mixing ratio of oil to S/CoS, play an important role in the formation of the nanoemulsion. For the development of a self-emulsified formulation, a right blend of low and high HLB (hydrophile lipophile balance) surfactant is necessary for the formation of a stable nanoemulsion. Therefore, high HLB surfactants (Polysorbate 80, Cremophore RH40, and Gelucire 44/14 with HLB value above 10.0) and a low HLB co-surfactant (Transcutol HP with a HLB of 4.2) were selected. It is important that the excipients used are listed as GRAS (generally regarded as safe) in the Handbook of Pharmaceutical Excipients (published by the American Pharmaceutical Association) or they have a history of use in marketed formulations. In the present study both, Peppermint oil alone and mixture of Peppermint oil and Triacetin (1:1) were tested for phase behaviour studies with Polysorbate80, Cremophore RH40 and Gelucire 44/14 as surfactants and Transcutol HP as the Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 225 Chapter 7 Summary cosurfactant to form S/CoS mixture. Based on solubility data, about 24 mg of Isotretinoin is soluble in 1 g of Peppermint oil. In order to maximize the drug loading capacity in minimum quantity of Peppermint oil, it was combined with Triacetin (1:1) to produce a similar solubility effect with less usage of Peppermint oil. The nanoemulsion existence area increased as the S/CoS ratio increased. Thus, an S/CoS ratio between 3:1 and 4:1 was selected for the formulation study. The selected S/CoS ratio between 3:1 and 4:1 were evaluated for titration after drug loading. Titration studies revealed that 3:1 S/CoS ratio produced microfine crystals upon standing. Surfactant is anticipated to enter the water phase and redistribute mainly between the water phase and the emulsion-water interface, resulting in a loss of solvent capacity of the vehicle. Thus, the problem of precipitation was solved by increasing the surfactant proportion (S/CoS [4:1]) in the system. As seen from the ternary plot, Peppermint oil alone or in combination with Triacetin in the ratio of 1:1 with Polysorbate 80 as the surfactant and Transcutol HP as the cosurfactant gave a wider nanoemulsion region at a S/CoS ratio of 4:1. Thus, Peppermint oil alone or in combination with Triacetin in the ratio of 1:1 with Polysorbate 80 as the surfactant and Transcutol HP as the cosurfactant was selected as the preferred vehicle for the optimized formulation. The inclusion of drug narrowed the nanoemulsion existence area, because inclusion of the drug in the lipid phase led to expansion of the lipid phase and consequently a need for a higher S/CoS ratio for stabilization. A series of SNEDDS formulations were prepared using Polysorbate-80, Cremophore RH40, and Gelucire 44/14 as surfactants and Transcutol HP, PEG 600 and Tetraglycol as the cosurfactants in the S/CoS ratio of 4:1. Peppermint oil and Triacetin were used as oils; Peppermint oil was used either alone or in combination with Triacetin in the ratio of 1:3 and 1:1 (Peppermint oil/Triacetin). Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 226 Chapter 7 Summary The components were mixed by gentle stirring and vortex mixing. The contents were heated upto 40ºC on a magnetic stirrer and then sonicated for 10 minutes in Ultrasonic bath until Isotretinoin was perfectly dissolved. The preparation obtained (equivalent to 20 mg Isotretinoin) were filled into hard gelatin size ‘0’ capsules. The filled capsules were stored at room temperature until their use in subsequent studies. It was observed that a decrease in the proportion of Peppermint oil in the composition (Peppermint oil/Triacetin (1:3)) resulted in generation of nonclear dispersion. This could be due to loss of solvent capacity of Triacetin. Thus the problem of precipitation was solved by increasing the proportion of Peppermint oil in the system (Peppermint oil/Triacetin (1:1)). It was also observed that only Transcutol as cosurfactant produced a clear dispersion when compared to the other cosurfactants employed. This may be attributed to its fluid like property which may easily penetrate and occupy the sphere like gap between the interfacial surfactant molecules. It was observed that Peppermint oil alone or in combination with Triacetin in the ratio of 1:1 as oil, Polysorbate-80 as surfactant and Transcutol HP as co surfactant gave the highest drug loading capacity which was taken for further evaluation. It can be seen that there is a correlation between the drug content and clarity of the SNEDDS formulations. Those formulations which had the highest self emulsification gave maximum drug loading. Nanoemulsions are characterized by the droplet size in nanometer size range. Therefore particle size analysis was performed to see whether the resultant emulsions are indeed nanoemulsions. The selected formulations were in the size range of 100 – 150 nm. The amount of Isotretinoin dissolved in 45 min (t45 values) increases when the particle size decreased. Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 227 Chapter 7 Summary It is clear that increasing the concentration of both surfactant and cosurfactant lead to decreasing particle size which means that the particle size distribution is inversely proportional to the concentration of surfactant and cosurfactant. An increase in the ratio of the oil phase (Peppermint oil) resulted in a proportional increase in particle size, because of the simultaneous decrease in the S/CoS proportion. It is well known that the addition of surfactants to the nanoemulsion systems causes the interfacial film to stabilize and condense, while the addition of cosurfactant causes the film to expand; thus, the relative proportion of surfactant to cosurfactant has varied effects on the droplet size. Therefore, using a proper ratio of surfactant and co-surfactant results in production of formulation in nano range particle size. Turbidity values have been reported to be of use in SNEDDS characterization. It can be seen that there is a good correlation between the visual observation and turbidity of all formulations. It can be observed that there is a correlation between the viscosities and the rate of dissolution of the drug from the formulation. The formulation which had the lowest viscosity showed a faster onset on drug release. FT-IR spectrums were mainly used to determine if there was any interaction between the drug and any of the excipient used. The presence of interaction was detected by the disappearance of peaks corresponding to important functional groups of the drug. Isotretinoin compatibility with the ingredients of self-nanoemulsified formulations was tested using FT-IR. The absorbance spectrums of Isotretinoin showed several characteristic peaks. The spectrum of Isotretinoin SNEDDS formulation had the feature of each of the components and did not change the infrared spectrum of Isotretinoin. This indicated that there is no chemical interaction in the ternary system and that the molecular structure of Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 228 Chapter 7 Summary Isotretinoin remained completely intact. Therefore Isotretinoin did not interact with any one of the self-nanoemulsified components. The release of Isotretinoin from the investigated SNEDD formulations was markedly different from one formulation to another. Drug release from the SNEDD formulations was found to be significantly higher as compared with that of conventional marketed formulation (soft gel capsules). It could be suggested that the SNEDD formulation resulted in spontaneous formation of a nanoemulsion with a small droplet size, which permitted a faster rate of drug release into the aqueous phase, much faster than that of marketed formulation. Thus, this greater availability of dissolved Isotretinoin from the SNEDD formulation could lead to higher absorption and higher oral bioavailability. Freeze thawing process showed that there was very slight recrystallization at freezing temperature. So in order to solve this stability issue, solidifying agents such as PEG 6000 and Poloxamer 407 were added to the SNEDDS formulation to make a semisolid composition. It was observed that there was no significant change in the drug release by adding solidifying agents. However it was observed that PEG 6000 had better solidifying capacity and faster drug release. Based on the above findings, the final composition with solidifying agent PEG 6000 was prepared and subjected for stability studies. Generally, SNEDD formulations are put into hard gelatin capsules as the final dosage form. However, liquid-filled hard gelatin capsules are susceptible to leakage, and the entire system has a very limited shelf life owing to its liquid characteristics and the possibility of precipitation of the drug from the system. Thus, the developed formulation with solidifying agent PEG 6000 was subjected to stability studies to evaluate its stability and integrity of the dosage form. The Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 229 Chapter 7 Summary formulation was found to be stable for 6 months at accelerated conditions and 12 months at long-term conditions. There was no significant change in the drug content, drug release (t90%), or particle size of the resultant nanoemulsion. It was observed that the related impurities were very minimal at the end of accelerated stability which proves that peppermint oil as carrier enhanced the stability of the composition without the need for any antioxidants in the formulation. It was also seen that the formulation was compatible with the hard gelatin capsule shells, as there was no sign of capsule shell deformation. There were also no significant changes in the appearance or nanoemulsifying property. Furthermore, the formulation was found to show no phase separation, drug precipitation, or capsule leaks. Thus, these studies confirmed the stability of the developed formulation and its compatibility with hard gelatin capsules. The results of bioavailability studies showed that the SNEDDS composition containing 10 mg of the active showed a 6-fold increase in the relative bioavailability. The idea of fast release was proved in this study by the fact that the maximum concentration for the test product was at 1.0 hour compared to 2.67- 4.0 hours for the reference product with less inter subject variability. The novel composition of Isotretinoin achieved its goal in providing a enhanced bioavailability and significantly shorter Tmax, which suggests a reduction in the regular dose of this drug to potentially eliminate its side effects. Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 230