Experimental substantiation of the composition of gelatin mass for obtaining capsules with essential oils

Introduction. Soft gelatin capsules are a promising dosage form comprising essential oils as active agents. Joint research of the staff of the Perm State Pharmaceutical Academy, the Research Institute of Nutrition of the Ministry of Energy and Industry of the Republic of Tajikistan have proposed the composition of gelatin mass for encapsulation by the rotary matrix method. The mechanical and physical-technological parameters required to preserve the strength and elasticity of the capsule shell during the production process and storage are determined.Aim. Study of the rheological properties of gelatin masses based on gelatin of different grades, as well as the migration of essential oils through capsule shells.Materials and methods. Pharmaceutical active substances "Lipovitol" and "Limoneol" obtained in the Republic of Tajikistan were used as active substances introduced into the composition of soft gelatin capsules. Sunflower oil was used as the solvent. Gelatin samples were used to obtain gelatin masses: 1 – Foodchem (China), 2 – Brodnickie Zaklady Zelatyny Sp. zo.o. (Poland), 3 - Italgelatine s.p.a. (Italy), 4 – Ewald-Gelatine GmbH (Germany), 5 – Weishardt International (France); glycerol; sunflower oil. Gelatin mass for manufacturing soft capsules was prepared in a closed reactor. Capsules were prepared on an automatic encapsulation line RJWJ – 115 Soft Gelatin Encapsulator Machine (China). The structural and mechanical properties of soft gelatin masses were determined on a rotary viscometer RV type "Reotest 2" (Germany). The dynamics of the process of migration of essential oils and its components were studied by changing their amount in a capsule by chromato-mass spectrometry method on a chromatograph Varian CP 3800 with a quadrupole mass spectrometer 4000 MS as a detector (USA).Results and discussion. When studying the rheological properties of model compositions, it was found that for all samples of gelatin masses there is a decrease in values of effective viscosity when the shear rate increases, which characterizes the tested samples as a structured dispersion system. Additional studies have shown that the gelatin masses have thixotropic properties. Samples of gelatin masses 3–5 had narrower hysteresis loops, while sample 5 the narrowest, restoration of the structure took place quite quickly. Capsules obtained from gelatin mass 3 and 4 samples had a strong seam and were well cut out of the tape. From the mass of sample 5, high strength ribbons were obtained, a high temperature was required to seal the capsules, in some capsules the seam was not glued on one side, as a result, the capsules were rigid and brittle. As a result of the study, the rheological optimum of the gelatin mass suitable for preparing capsules by a rotary matrix method was determined, which has boundaries in the ranges of shear rates of 0.556–243 s-1 and viscosity ranges of 11.46-5028.76 Pa ⋅ s and shear stress of 2788–2808 Pa developing at these rates. When studying the migration of active substances through the capsule shell, it was found that over three years of storage of capsules in a closed polymer can, the content of essential oil in Lipovitol capsules decreased by 4.88 %, in Limoneol capsules by 5 %, which indicates partial migration of oil through the gelatin shell. The content remained within the permissible deviations (±10 %). The content of essential essential oil components also remained within acceptable deviations throughout the shelf life.Conclusion. The optimal composition of the shell for producing soft capsules by a rotary matrix method is justified. It was found that the rheological optimum of gelatin mass is characterized by viscosity ranges of 11.46-5028.76 Pa ⋅ s and shear stress of 2788–2808 Pa. According to the results of the study of the migration of essential oils through the shell, has been established the shelf life of soft gelatin capsules in glass jars made of dark glass and a temperature of 15 to 25 °C – 3 years.

Development of platform technology for gastro-resistant soft gel capsules by using the cross-linking technique

Introduction: Conventional enteric coating is very challenging in soft gel capsules because of shell nature (smooth surfaces and elasticity). Soft gelatin capsules are highly sensitive to temperature, humidity and it can lose their tensile strength during the conventional coating process. Materials and Methods: Enteric soft gel capsules were prepared by addition of enteric polymer in the gelatin shell composition by inducing the cross linking of gelatin through chemical treatment. Results: This dual approach makes the soft gelatin capsules to resist the drug release in stomach and reliably release their contents in the intestine within a predetermined time without affecting the physical properties of soft gel capsules. Conclusions: Enteric effect of soft gel capsules are brought by a specialized synergetic technique which is unique for the molecules which need intestinal drug release.

An oral lipidic native testosterone formulation that is absorbed independent of food

Context: There is no licensed oral Native Testosterone (NT) because of challenges in formulation. Licensed oral formulations of the ester, testosterone undecanoate (TU), require a meal for absorption and generate supraphysiological dihydrotestosterone (DHT) levels. Objective: To develop an oral NT formulation. Design and Methods: A lipid-based formulation of native testosterone filled into soft-gelatin capsules at 40mg per capsule was designed with 2 years stability at ambient temperature. Pharmacokinetic comparison studies of this oral lipidic NT formulation to oral TU were conducted in dogs and hypogonadal men. Results: In dogs, 40mg NT was well absorbed under fasted conditions whereas 40mg TU required a high fat meal: for NT the mean fed / fasted AUC ratio was 1.63 and for TU 7.05. In hypogonadal men fed and fasted NT had similar pharmacokinetics: Cmax mean 26.5 vs 30.4 nmol/l (769 vs 882 ng/dl), AUC0-10h 87 vs 88.6 h*nmol/l. NT (fed state) showed a testosterone AUC increase of 45% between 120mg and 200mg and NT 200mg gave a similar mean AUC0-10h to TU 80mg: 87 vs. 64.8 h*nmol/l. Serum TU levels were variable and on a molar basis were ~10-fold higher than serum testosterone levels after TU 80mg fed. The DHT:testosterone AUC0-10h ratio was more physiological for NT than TU being 0.19 vs 0.36. There were no emerging safety concerns with NT. Conclusion: This novel oral lipidic native testosterone formulation has potential advantages over oral TU of dosing independent of food and a lower risk of supraphysiological DHT levels.

A Survey of the Regulatory Requirements for the Waiver of In Vivo Bioequivalence Studies of Generic Products in Certain Dosage Forms by Participating Regulators and Organisations of the International Pharmaceutical Regulators Programme

The requirements to waive in vivo bioequivalence studies for immediate release solid oral dosage forms based on the Biopharmaceutics Classifications System (BCS) are well known, and biowaivers[1] for other types of oral dosage forms based on pre-defined criteria may also be acceptable. Similarly, biowaivers for dosage forms such as injectable products may also be allowed if certain criteria are met. The current paper summarises the biowaiver requirements for oral solutions and suspensions, soft gelatin capsules and injectable products (intravenous injections, subcutaneous and intramuscular injections, emulsions for injection and micellar solutions for injection) among the participants of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP). A review of the requirements indicated that there was a trend towards convergence when the dosage form became less complex; however, the most common approach used by each of the jurisdictions was a case-by-case approach given that most jurisdictions do not have well defined guidelines to support all possible scenarios. Even in the simplest case of intravenous solutions, the acceptability of qualitative changes in excipients differ between the IPRP members. Notwithstanding the differences, the dissemination of the information is a first step towards regulatory convergence regarding biowaivers for certain dosage forms and should be useful for pharmaceutical companies currently developing generic medicinal products for IPRP jurisdictions.

Challenges of Dissolution Methods Development for Soft Gelatin Capsules

Recently, the development of soft gelatin capsules (SGCs) dosage forms has attracted a great deal of interest in the oral delivery of poorly water-soluble drugs. This is attributed to the increased number of poorly soluble drugs in the pipeline, and hence the challenges of finding innovative ways of developing bioavailable and stable dosage forms. Encapsulation of these drugs into SGCs is one of the approaches that is utilized to deliver the active ingredients to the systemic circulation to overcome certain formulation hurdles. Once formulated, encapsulated drugs in the form of SGCs require suitable in vitro dissolution test methods to ensure drug product quality and performance. This review focuses on challenges facing dissolution test method development for SGCs. A brief discussion of the physicochemical and formulation factors that affect the dissolution properties of SGCs will be highlighted. Likewise, the influence of cross-linking of gelatin on the dissolution properties of SGCs will also be discussed.

Clinical efficacy of different dosage forms containing vitamin D: design and study outcomes of a randomized, comparative clinical trial

<p class="abstract"><strong>Background:</strong> Different dosage forms of vitamin D like tablets, soft gelatin capsules, oral granules, powders, solutions and thin films are available. The objective of the present study was to evaluate and compare the clinical efficacy of three different dosage forms of vitamin D3 namely, orally disintegrating strips, oral granules and oral solution.</p><p class="abstract"><strong>Methods:</strong> An open label, single centre, prospective, randomized, parallel group, comparative study was conducted for a period of 4 months. The study participants were divided into three groups (A, B, C) and received the respective treatments (orally disintegrating strips, n=20; granules, n=20; oral nano solution, n=10) for the study period. The estimation of blood levels of 25-hydroxy vitamin D [25(OH)D₃] in all the subjects at day 0, 60 and 120 was carried out.</p><p class="abstract"><strong>Results:</strong> The normalization level of 25(OH)D₃achieved by the subjects in group A, group B and group C was 100%, 83.3% and 90% respectively after 90 days. Comparison of 25(OH)D₃level in all three groups showed significant increase at day 60. The levels were maintained at day 90 and 120 even after drastic reduction in dosage in Group A and group C. On day 120, the dose reduction was in the order of group A&gt;group C&gt;group B.</p><p class="abstract"><strong>Conclusions: </strong>All the three formulations showed increase in the level of 25(OH)D_3.It can be concluded that oral disintegrating strips of 25(OH)D₃ are clinically more efficient than other conventional dosage forms.</p>

COMPARATIVE STUDY ON CLINICAL EFFICACY AND SAFETY OF FORMULATED AND MARKETED MYRRH EXTRACT IN CAPSULES

Objective: The development of myrrh extract from natural origin capable of eradicating schistosomal infection has gained the interest of many scientists. Recently, myrrh extract is considered as the drug of choice from natural origin used to treat schistosomiasis. This study was performed to evaluate the safety and efficacy of hard gelatin capsules of myrrh extract in the treatment of Schistosoma mansoni compared to Mirazid which is the only herbal drug present in the market. Methods: In the present study, the clinical evaluation of different doses of formulated myrrh extract hard gelatin capsules against different grades of S. mansoni infections (mild, moderate, and heavy) was carried out and compared with marketed soft gelatin capsules Mirazid. Results: In all types of S. mansoni infection, it was clear that the efficacy of n-hexane and alcohol myrrh extracts hard gelatin capsules was higher than or equal to that of Mirazid soft gelatin capsules. Conclusion: Hard gelatin capsules of myrrh extract (mixed doses) are more effective and more economic as a pharmaceutical dosage form for pharmaceutical manufacturers than Mirazid soft gelatin capsules. Consequently, with its lower price, it can reach the poor patient which is the main patient of schistosomiasis.