Prescription design of raloxifene nanoemulsion / 中国药学杂志

OBJECTIVE:To study formulation design of raloxifene nanoemulsion. METHODS: The solubilities of raloxifene in excipients of nanoemulsion were investigated. On the basis, emulsifier and oil were selected by the emulsifying ability. The combination and optimum proportion among co-emulsifier, oil and emulsifier were determined by the pseudo-ternary phase diagram. The effect of raloxifene on nanoemulsion prescription was studied by drug loading. Finally chitosan and carboxylated chitosan were used to regulate the Zeta potential of raloxifene nanoemulsions. RESULTS: The optimum formulation ratio of LOA, IPP, RH40 and ethanol for loading 15 mg raloxifene is 0.167 g∶0.333 g∶0.3 g∶0.2 g, respectively. The Zeta potentials of the nanoemulsions can be changed by chitosan and carboxylated chitosan from -0.954 mV to 20 mV and -13 mV or so,respectively. The effect of different pH and dilution times on stability of formulations were slight. CONCLUSION: The formulations of raloxifene nanoemulsion including positive, negative and near zero Zeta potential were obtained, which have laid a foundation for absorption mechanism study of the raloxifene nanoemulsion.

Formulation design, absorption mechanism and bioavailability of nanoemulsions for enhancing oral absorption of raloxifene / 药学学报

Oral formulations of nanoemulsions (NE) were systematically designed, and then their effects on oral absorption of raloxifene (RAL), including their absorption mechanisms were investigated. RAL solubility in water and various excipients of NE and oil-water partition coefficient[P(O/W)] of RAL were examined. Next the optimal compatibility between emulsifiers and oils in NE were ascertained by emulsification ability. Proportions of each component and optimal RAL-NE were fully confirmed by a pseudo-ternary phase diagram and drug loading, respectively. RAL-NE quality was evaluated by particle size, zeta potential, morphology, entrapment efficiency and stability in simulated gastrointestinal fluid. A MDCK cell model was used to study the in vitro transport mechanism of RAL-NE. Oral bioavailability of RAL-NE was eventually performed in SD rats. RAL can be classified as BCSⅡ based on the solubility and P(O/W). The best formulation of RAL-NE was composed of linoleic acid (LOA):isopropyl palmitate (IPP):cremophor RH40 (RH40):alcohol as 1.67:3.33:3:2. Drug loading in pre-nanoemulsion was 15 mg·g-1 andentrapment efficiency of RAL in NE was (79.4 ±0.4)%. The particle size, zeta potential and drug content of RAL-NE were maintained in the simulated gastrointestinal fluid. The in vitro transport mechanism of RAL-NE in MDCK cells was mainly clathrin-mediated endocytosis. The oral bioavailability of RAL in RAL-NE relative to RAL-suspension was 171.9%. The best formulation of RAL-NE studied systematically was confirmed to significantly improve the RAL absorption by in vitro and in vivo evaluations (P < 0.05). This paper provides references for oral NE research and development.

Desarrollo tecnológico y estudio de estabilidad de una formulación de oxaliplatino 100 mg, solución inyectable / Technological development and stability study of a 100 mg oxaliplatinum formulation in injectable solution

Introducción: el oxaliplatino, es un análogo de los complejos derivados del platino en el cual el átomo de platino central está rodeado por un oxalato y en posición trans el 1,2‒diaminociclohexano. La cinética de enlace del oxaliplatino sobre el ADN se produce en 15 minutos como máximo y en comparación con el cisplatino presenta una cinética bifásica de 4 a 8 horas y demuestra mayor eficacia sobre ciertos tumores. Objetivo: diseñar una formulación de oxaliplatino, solución inyectable, conteniendo 100 mg del ingrediente activo por bulbo, que cumpla con los índices de calidad para esta forma farmacéutica y proporcione el efecto terapéutico deseado. Métodos: se realizaron los estudios de formulación correspondientes y se ensayaron cinco variantes tecnológicas, en las que se ajustó el pH de la formulación según las exigencias de un preparado parenteral. Se efectuó un estudio de temperatura, para lograr la disolución del principio activo, sin que se afectaran sus propiedades, dada su poca solubilidad en medio acuoso. Se estudiaron diferentes materiales de envase y temperaturas de conservación del producto, además se estandarizó una técnica analítica por Cromatografía Líquida de Alta Resolución para la estabilidad de la formulación, determinar su fecha de vencimiento y para su control de la calidad. Resultados: el desarrollo tecnológico resultó satisfactorio, en una de las variantes ensayadas, se obtuvo un producto que cumple con todas las especificaciones descritas en la monografía para el control de la calidad del preparad, mantiene sus propiedades físicas, químicas y microbiológicas inalterables por un período de 18 meses, almacenada a temperatura ambiente, con un escalado a nivel piloto, sin que se presentaran problemas tecnológicos. Conclusiones: se obtuvo la formulación de un medicamento en forma de solución inyectable, que contiene oxaliplatino como principio activo, que cumple con todas las especificaciones de calidad para este tipo de forma farmacéutica, lo que aumenta arsenal terapéutico de Cuba(AU)

Introduction: oxaliplatinum is an analogue of the platinum-derived complexes in which the central platinum atom is surrounded by an oxalate and 1,2?diaminocyclohexane in transposition. The link kinetics of oxaliplatinum on the DNA occurs in 15 minutes at most and if compared with the cysplatinum, it presents a 4-8 h biphasic kinetics and higher efficacy over certain tumors. Objective: to design an oxaliplatinum formulation, for injection solution that contains 100mg of the active ingredient per ampoule, comply with the quality parameters for this pharmaceutical form and provides the desired therapeutic effect. Methods: the corresponding formulation studies were performed together with the testing of five technological variants in which the formulation pH was adjusted according to the requirements of a parenteral product. A temperature study was also conducted to reach dissolving the active principle without any damage to its properties, given that it is poorly water-soluble. Different packing materials and storage temperatures of the product were studied in addition to standardizing an analytical technique based on high performance liquid chromatography for the stability of the formulation, estimation of the expiry date and for the quality control. Results: the technological development was satisfactory in one of the tested variants. The obtained product complied with all the described specifications in the monograph for the quality control of the product; its physical, chemical and microbiological properties remained unchanged for a period of 18 months and stored at room temperature, with pilot scale-up with no further technological problems. Conclusions: there was obtained the formulation of a drug in its injectable form that contains oxaliplatinum as active ingredient, complies with all the quality specifications for this pharmaceutical form and increases the therapeutical arsenal available in Cuba(AU)

Desarrollo tecnológico de una solución oftálmica de latanoprost para el tratamiento del glaucoma / Technological development of latanoprost eye solution for treatment of glaucoma

Introducción: el latanoprost, análogo de la prostaglandina F2α, es un agonista selectivo del receptor FP prostanoide que reduce la presión intraocular por incremento del flujo del humor acuoso, se clasifica como un antiglaucomoso y se indica en el tratamiento del glaucoma de ángulo abierto y la hipertensión ocular. Objetivo: se diseñó una formulación de uso oftálmico conteniendo latanoprost como sustancia activa, a una concentración de 500 µg/mL, que cumpla con los índices de control de calidad para esta forma farmacéutica y proporcione el efecto terapéutico deseado. Métodos: se realizaron los estudios de formulación y se ensayaron nueve variantes tecnológicas, seleccionándose la composición y procedimiento tecnológico más adecuados para su posterior escalado en la industria. Se ajustó el pH empleando la trometamina y la isotonicidad, con manitol, según las exigencias de una formulación oftálmica. Se desarrolló y validó una técnica analítica por Cromatografía Líquida de Alta Resolución para estudiar la estabilidad, determinar su fecha de vencimiento y para efectuar el control de la calidad de la formulación. Resultados: el desarrollo tecnológico, resultó satisfactorio, se obtiene una formulación que cumple con todas las especificaciones descritas en la técnica desarrollada por el fabricante, para el control de la calidad del producto. Se comprobó que la preparación mantiene sus propiedades físicas, químicas y microbiológicas inalterables por un período de 24 meses, almacenada a una temperatura controlada entre 2 y 8 °C y protegido de la luz. El escalado a nivel piloto no reveló problemas tecnológicos y resultó no irritante, según el criterio establecido por la Unión Europea para la irritabilidad oftálmica. Conclusiones: se obtuvo una formulación de colirio de latanoprost, útil en el tratamiento del glaucoma, con todas las especificaciones de calidad para este tipo de forma farmacéutica, con lo que pudiera aumentarse el arsenal terapéutico de Cuba(AU)

Introduction: latanoprost, F2α prostaglandine analogue, is a selective FP receptor Prostanoide agonist that reduces the intraocular pressure due to increase of aqueous humor; it is classified as an anti-glaucoma drug and indicated for the treatment of open angle glaucoma and eye hypertension. Objective: aformula for ophthalmic uses was designed, which contains latanoprost as active ingredient at concentration of 500 µg/mL and complies with the quality control indexes for this pharmaceutical form and provides the desired therapeutic effect. Methods: the formulation studies were conducted and nine technological variants were tested; the most adequate composicion and technological procedure was selected for further industry scaling. The pH index and isotonicity were then adjusted using trometamin and manitol, respectively according to the demands of the eye formulation. A high resolution liquid chromatography-based analytical technique was developed and validated to study the stability, to determine the expiry date and to make the quality control of the formulation. Results: the technological development proved to satisfactory since this formulation complies with all the specifications described in the manufacturer's technique for the quality control of the product. It was confirmed that this preparation keeps its physical, chemical and microbiological properties unchanged for 24 months if stored at 2-8 ºC and protected from light. Pilot scale-up did not show either technological problem or irritating effect according to the European Union criteria for eye irritability. Conclusions: there was attained a latanoprost eye drop formulation for the treatment of glaucoma, which complies with all the quality specifications for this type of pharmaceutical form and could increase the therapeutic arsenal in Cuba(AU)

Desarrollo tecnológico de una formulación de betaxolol 0, 5 por ciento para administración oftálmica / Technological development of 0. 5 percent Betaxolol formulation for ophthalmological use

Introducción: el clorhidrato de betaxolol es un bloqueador cardioselectivo ß1 adrenérgico, que no presenta una actividad significativa como estabilizante de membrana (anestésico local) y carece de actividad simpaticomimética intrínseca. A nivel ocular actúa disminuyendo la producción de humor acuoso, reduciendo la presión intraocular a niveles normales, ya sea acompañada o no de glaucoma. Está indicado en el tratamiento del glaucoma crónico de ángulo abierto en pacientes con presión intraocular elevada (hipertensión ocular). Objetivo: diseñar una formulación de betaxolol 0,5 por ciento colirio, que cumpla con los índices de control de calidad para esta forma farmacéutica y que proporcione el efecto terapéutico deseado. Métodos: se realizaron cuatro variantes tecnológicas, modificando convenientemente las cantidades de excipientes y manteniendo la del principio activo, para lo que se tuvo en cuenta la composición de la formulación líder, con la finalidad de seleccionar la de mejor estabilidad en 3 meses de seguimiento. Se ajustó el pH y la isotonicidad de la formulación, según las exigencias de un preparado oftálmico. La isotonicidad se alcanzó con cloruro de sodio. Resultados: el desarrollo tecnológico de la formulación resultó satisfactorio, y se obtuvo un producto que cumplió con todas las especificaciones descritas en la USP 30, para el control de la calidad del producto. La preparación mantuvo sus propiedades físicas, químicas y microbiológicas inalterables por un período de 24 meses, almacenada a una temperatura de 30,0 ± 2,0 °C. Conclusiones: la formulación de un medicamento obtenida en forma de colirio que contiene betaxolol clorhidrato como principio activo para el tratamiento del glaucoma, cumple con todas las especificaciones de calidad para este tipo de forma farmacéutica, lo cual puede aumentar el arsenal terapéutico de Cuba

Introduction: Betaxolol chlorhydrate is a cardioselective adrenergic ß1 blocker that does not play a significant role as membrane stabilizer (local anesthestic) and lacks intrinsic sympathomimetic activity. It diminishes the production of aqueous humor in the eye, thus reducing the intraocular pressure to normal, either with or without glaucoma. This drug is indicated in the treatment of chronic open angle glaucoma affecting patients with ocular hypertension. Objective: to design a formulation of 0.5 por ciento Betaxolol eye drops that meets the quality control parameters for this pharmaceutical form and that provides the desired therapeutic effect. Methods: four technological variants were performed by adequately modifying the excipient quantities and by keeping the active principle amount, for which the composition of the leading formulation was taken into account. The aim was to select the most stable variant after 3-month follow-up. The pH and the isotonicity of the formulation were adjusted for the requirements of an ophthalmologic preparation. The isotonicity was reached with sodium chloride. Results: the technological development of this formulation was satisfactory; the final product met all the specifications for the quality control of the product as described in USP 30. The physical, chemical and microbiological properties of the preparation remained unchanged for 24 months under storage conditions of 30.0 ± 2.0 °C. Conclusions: the formulation of a medical eye drops containing Betaxolol chlorhydrate as active principle, meets all the quality specifications for this pharmaceutical form to treat glaucoma, which may expand the therapeutic options in Cuba

Desarrollo tecnológico de una formulación de diclofenaco de sodio 0, 1 por ciento para administración oftálmica / Technological development of a 0.1 percent sodium diclophenac formulation for opththalmological use

Introducción: el diclofenaco de sodio es un derivado del ácido fenilacético que pertenece al grupo de los antiinflamatorios no esteroideos con propiedades antirreumáticas, antiinflamatorias, analgésicas y antipiréticas pronunciadas. Al nivel ocular se indica para el tratamiento de conjuntivitis, queratoconjun­tivitis, úlceras corneales, y en el de inflamación de la córnea y la conjuntiva por traumatismos. Además, es empleado en la inflamación subsecuente a la cirugía de cataratas y para inhibir la miosis intraoperativa y el edema macular cistoide posoperativo. Objetivo: diseñar una formulación de diclofenaco de sodio 0,1 por ciento colirio, que cumpla con los índices de control de calidad para esta forma farmacéutica y que proporcione el efecto terapéutico deseado. Métodos: se realizaron cinco ensayos tecnológicos en los que se ajustó el pH y la isotonicidad de la formulación según las exigencias de un preparado oftálmico. La isotonicidad se ajustó con ácido bórico y el pH de máxima estabilidad se logró empleando la trometamina. Resultados: el desarrollo tecnológico de la formulación resultó satisfactorio, y se obtuvo un producto que cumplió con todas las especificaciones descritas en la técnica desarrollada por el fabricante para el control de la calidad del producto. La preparación mantuvo sus propiedades físicas, químicas y microbiológicas inalterables por un período de 12 meses, almacenada a una temperatura controlada por debajo de 25 °C. Conclusiones: la formulación de un medicamento obtenida en forma de colirio, que contiene diclofenaco de sodio como principio activo, empleado en diferentes afecciones al nivel ocular, cumple con todas las especificaciones de calidad para este tipo de forma farmacéutica, lo cual puede aumentar el arsenal terapéutico de Cuba

Introduction: Sodium diclophenac derives from the phenylacetic acid belonging to the non-steroid anti-inflammatories that have notable anti-rheumatic, anti-inflammatory, analgesic and antipyretic properties. It is prescribed to treat conjunctivitis, keratoconjunctivitis, corneal ulcers, corneal and conjunctival inflammation due to traumas. Additionally, it is used in reducing inflammation after the cataract surgery and in inhibiting the intraoperative myosis and the postoperative cystoid macular edema. Objective: to design a formulation of 0.1 percent sodium diclophenac eye drops that meets the quality control parameters for this pharmaceutical form and that provides the desired therapeutic effect. Methods: five technological assays were conducted to adjust for the pH and the isotonicity of the formulation as required for an ophthalmologic preparation. Isotonicity was adjusted with boric acid, and Trometamin served to obtain highly stable pH. Results: the technological development of the formulation was satisfactory. There was obtained a product that met all the specifications described in the manufacturer's technique for the quality control. The physical, chemical and microbiological properties of the preparation remained unchanged for 12 months under storage conditions below 25 °C. Conclusions: the eye drop formulation, with sodium diclophenac as active principle, meets all the quality specifications for this pharmaceutical form to treat various eye diseases. This might broadens the therapeutic options in Cuba

Optimization of the Formulation of Paeonol-SPE_7-?-CD Inclusion Complex Tablets / 中国药房

OBJECTIVE:To optimize the formulation of paeonol-SPE7-?-CD inclusion complex tablets.METHODS:The formulation was optimized by orthogonal test with dissolution rate serves as index and the amount of adhesive(10% starch paste),disintegrant(dry starch)and lubricant(magnesium stearate)served as major factors,meanwhile a verification test was conducted.RESULTS:The optimum formulation of paeonol-SPE7-?-CD inclusion complex tablets was as follows:paeonol-SPE7-?-CD 106.2 g,lactose 48.7 g,10% starch paste 3.0 g,dry starch 6.0 g,and magnesium stearate 0.1g.The mean dissolution rate was 95.56% for three batches of samples prepared under the above condition.CONCLUSION:The optimized formulation is ideal and feasible.

Formulation and characteristics of self-microemulsifying drug delivery system for breviscapine / 中草药

Objective To study formulation and characteristics of self-microemulsifying drug delivery system for breviscapine(BRV-SMEDDS).Methods The optimum formulations of BRV-SMEDDS were screened by solubility tests,formula compatibility,and pseudo-ternary phase diagrams.And the physicochemical characters,dissolution in vitro and in situ rat's intestine absorption of BRV-SMEDDS were also observed.Results The optimum formulation of SMEDDS was composed of Maisine 35-1-Cremophor RH40-PEG400-TEA=25∶40∶35∶7.The particle diameter was 88.6 nm.The percent of accumulated dissolution of BRV in SMEDDS in vitro was up to 97.8% at 1h,which was 8.0 times as much as that of BRV powder,and 5.1 times as BRV tablets.In the tests of in situ rat's intestine absorption,the permeability coefficient of BRV-SMEDDS was increased by 3.4 times as much as BRV powder,and 3.3 times as BRV tablets.Conclusion The dissolution and absorption of BRV is improved by formulation of SMEDDS.It could provide reference for the new dosage form of BRV.

Self-microemulsifying drug delivery system of flavonoids in hawthorn leaves / 中草药

Objective To develop the formulation of self-microemulsifying drug delivery system for hawthorn leaves flavonoids (HAW-SMEDDS). Methods The optimum formulations of oil phase, surfactant, and assistant surfactant for HAW-SMEDDS were screened by solubility test, compatibility test, and pseudo-ternary phase diagrams, with the time of formulating microemulsion, the consequence of visual examination, and particle size as indexes. The dissolution of HAW-SMEDDS was measured, taking the commercial tablet Yixintong Tablet as reference. Results The optimum self-microemulsifying drug delivery system was composed of Labrasol (35%), Transcutol P (10%). The particle diameter was (39.5?5.4) nm, the time of self-microemulsifying was less than 1 min. The percent of accumulated dissolution of hawthorn leaves flavonoids in SMEDDS in distilled water was up to 70% at 10 min, while that in the Yixintong Tablet was less than 50% at 60 min. Conclusion The formulation of HAW-SMEDDS preparation could meet the request of the design. It could provide the reference for the new dosage form.

Formulation design and vitro evaluation of self-microemulsifying drug delivery system / 中成药

90% in 20 min and more higher than the control tablets or capsule. CONCLUSION: The optimum formulation suits to slightly soluble drugs with different o/w distribution coefficient.It can provide reference for application of the SMEDDS the practical cases.