Manufacturing of a Lyophilized Parenteral Dosage Form of the Indoloquinone Antitumor Agent EO9 for Phase II Clinical Studies in the Setting of a Hospital Pharmacy

The manufacturing process for 28 batches (5555 vials) of a parenteral lyophilized dosage form of the investigational cytotoxic drug EO9 within the setting of a hospital pharmacy is described. Quality control of lyophilized EO9 indicated that all batches conformed to the specifications for the finished product. Long-term stability data of EO9 finished product are presented. In addition, the antimicrobial activity of EO9 against several microorganisms was determined. The implications of Good Manufacturing Practice (GMP) with respect to such a relatively large production in a small manufacturing site are discussed.     

Development of a lyophilized formulation for (R,R)-formoterol (L)-tartrate

(R,R)-formoterol is a beta-agonist for inhalation. Aqueous instability suggested the need for a reconstitutable lyophilized dosage form. The objective of these studies was to devise a stable, rapid-dissolving, therapeutically compatible dosage form. The effects of diluents and residual moisture on the stability of thermally stressed formoterol formulations were investigated. Drug and various excipients (acetate, lactose, and mannitol) were lyophilized and placed in humidity chambers (0 to 90% relative humidity) at 25 to 50 degrees C. Stability was characterized by time-dependent changes using HPLC, pH, and XRD. Residual moisture were determined by Karl Fisher methods. Regression models were developed to quantify the effects of formulation and environmental variation on drug stability. Solid-state instability was observed as a function of high residual moisture and diluent type. Although the residual moisture in mannitol formulations were typically below 1%, the degradation rate (50 degrees C) varied from 2 to 10 mcg/day, which was 1.3- to 20-fold high than observed for lactose formulations under the same relative humidity conditions. At high relative humidity, the presence of acetate significantly increased the degradation rate (p < 0.04). The critical residual moisture content for lactose formulations was 3%. The amount of lactose was optimized by evaluating the degradation over the temperature range 25 to 50 degrees C. Mannitol and acetate were shown to be unsuitable excipients, and an optimal lactose amount was 50 mg for vials containing 50 mcg of drug.     

Development of a Lyophilized Formulation for (R,R)-Formoterol (L)-Tartrate

(R,R)-formoterol is a β-agonist for inhalation. Aqueous instability suggested the need for a reconstitutable lyophilized dosage form. The objective of these studies was to devise a stable, rapid-dissolving, therapeutically compatible dosage form. The effects of diluents and residual moisture on the stability of thermally stressed formoterol formulations were investigated. Drug and various excipients (acetate, lactose, and mannitol) were lyophilized and placed in humidity chambers (0 to 90% relative humidity) at 25 to 50°C. Stability was characterized by time-dependent changes using HPLC, pH, and XRD. Residual moistures were determined by Karl Fisher methods. Regression models were developed to quantify the effects of formulation and environmental variation on drug stability. Solid-state instability was observed as a function of high residual moisture and diluent type. Although the residual moistures in mannitol formulations were typically below 1%, the degradation rate (50°C) varied from 2 to 10 mcg/day, which was 1.3- to 20-fold high than observed for lactose formulations under the same relative humidity conditions. At high relative humidity, the presence of acetate significantly increased the degradation rate (p < 0.04). The critical residual moisture content for lactose formulations was 3%. The amount of lactose was optimized by evaluating the degradation over the temperature range 25 to 50°C. Mannitol and acetate were shown to be unsuitable excipients, and an optimal lactose amount was 50 mg for vials containing 50 mcg of drug.     

Development of a Lyophilized Parenteral Pharmaceutical Formulation of the Investigational Polypeptide Marine Anticancer Agent Kahalalide F

Kahalalide F is a novel antitumor agent isolated from the marine mollusk Elysia rufescens; it has shown highly selective in vitro activity against androgen-independent prostate tumors. The purpose of this study was to develop a stable parenteral formulation of kahalalide F to be used in early clinical trials. Solubility and stability of kahalalide F were studied as a function of polysorbate 80 (0.1%-0.5% w/v) and citric acid monohydrate (5-15 mM) concentrations using an experimental design approach. Stabilities of kahalalide F lyophilized products containing crystalline (mannitol) or amorphous (sucrose) bulking agents were studied at +5°C and +30°C ±60% relative humidity (RH) in the dark. Lyophilized products were characterized by infrared (IR) spectroscopy and differential scanning calorimetry (DSC). Recovery studies after reconstitution of kahalalide F lyophilized product and further dilution in infusion fluid were carried out to select an optimal reconstitution vehicle. It was found that a combination of polysorbate 80 and citric acid monohydrate is necessary to solubilize kahalalide F. Lyophilized products were considerably less stable with increasing polysorbate 80 and citric acid monohydrate concentrations, with polysorbate 80 being the major effector. A combination of 0.1% w/v polysorbate 80 and 5 mM citric acid monohydrate was selected for further investigation. Lyophilized products containing sucrose as a bulking agent were more stable compared to the products containing mannitol. The glass transition temperature of the sucrose-based product was determined to be + 46°C. The amorphous state of the product was confirmed by IR analysis. A solution composed of Cremophor EL, ethanol, and water for injection (5%/5%/90% v/v/v CEW) kept kahalalide F in solution after reconstitution and further dilution with 0.9% w/v sodium chloride (normal saline) to 1.5 μg/m. A stable lyophilized formulation was presented containing 100 μg of kahalalide F, 100 mg sucrose, 2.1 mg citric acid monohydrate, and 2 mg polysorbate 80 to be reconstituted with a vehicle composed of 5%/5%/90% v/v/v CEW and to be diluted further using normal saline.     

Development of a Lyophilized Parenteral Pharmaceutical Formulation of the Investigational Polypeptide Marine Anticancer Agent Kahalalide F

Kahalalide F is a novel antitumor agent isolated from the marine mollusk Elysia rufescens; it has shown highly selective in vitro activity against androgen-independent prostate tumors. The purpose of this study was to develop a stable parenteral formulation of kahalalide F to be used in early clinical trials. Solubility and stability of kahalalide F were studied as a function of polysorbate 80 (0.1%–0.5% w/v) and citric acid monohydrate (5–15 mM) concentrations using an experimental design approach. Stabilities of kahalalide F lyophilized products containing crystalline (mannitol) or amorphous (sucrose) bulking agents were studied at +5°C and +30°C ±60% relative humidity (RH) in the dark. Lyophilized products were characterized by infrared (IR) spectroscopy and differential scanning calorimetry (DSC). Recovery studies after reconstitution of kahalalide F lyophilized product and further dilution in infusion fluid were carried out to select an optimal reconstitution vehicle. It was found that a combination of polysorbate 80 and citric acid monohydrate is necessary to solubilize kahalalide F. Lyophilized products were considerably less stable with increasing polysorbate 80 and citric acid monohydrate concentrations, with polysorbate 80 being the major effector. A combination of 0.1% w/v polysorbate 80 and 5 mM citric acid monohydrate was selected for further investigation. Lyophilized products containing sucrose as a bulking agent were more stable compared to the products containing mannitol. The glass transition temperature of the sucrose-based product was determined to be + 46°C. The amorphous state of the product was confirmed by IR analysis. A solution composed of Cremophor EL, ethanol, and water for injection (5%/5%/90% v/v/v CEW) kept kahalalide F in solution after reconstitution and further dilution with 0.9% w/v sodium chloride (normal saline) to 1.5 μg/m. A stable lyophilized formulation was presented containing 100 μg of kahalalide F, 100 mg sucrose, 2.1 mg citric acid monohydrate, and 2 mg polysorbate 80 to be reconstituted with a vehicle composed of 5%/5%/90% v/v/v CEW and to be diluted further using normal saline.     

Role of new Antioxidants in the Stabilization of Ophthalmic and ear Dosage form Preparation of Hamycin

The study involves the development of eye-ointment and ear-drop dosage form of hamycin, a polyene antifungal antibiotic, using anti-oxidants and stabilisers to enhance the stability of these dosage forms. It has been found that incorporation of hydroquinone (HQ), butylated hydroxy anisole (BHA), nordihydroguiaretic acid (NDGA), sodium deoxycholate (DSC) and ascorbyl palmitate (AP) in varying combinations in the dosage preparation have enhanced the stability and preserved physicochemical properties of the ointment for a period of 12 months period under refrigerated temperature (8+2°C) conditions. It was further observed that this dosage preparation is more stable in polyethylene glycol bases than in lanolin bases. Ear-drops dosage preparation has shown stability for 12 months period in the presence of BHA and in combination of other antioxidants under refrigerated temperature. However, ear-drops dosage form was found to be stable only for a period of 6months in ambient condition. It is therefore, recommended that these dosage preparations be stored in refrigerated conditions.     

Role of new Antioxidants in the Stabilization of Ophthalmic and ear Dosage form Preparation of Hamycin

Abstract

The study involves the development of eye-ointment and ear-drop dosage form of hamycin, a polyene antifungal antibiotic, using anti-oxidants and stabilisers to enhance the stability of these dosage forms. It has been found that incorporation of hydroquinone (HQ), butylated hydroxy anisole (BHA), nordihydroguiaretic acid (NDGA), sodium deoxycholate (DSC) and ascorbyl palmitate (AP) in varying combinations in the dosage preparation have enhanced the stability and preserved physicochemical properties of the ointment for a period of 12 months period under refrigerated temperature (8+2°C) conditions. It was further observed that this dosage preparation is more stable in polyethylene glycol bases than in lanolin bases. Ear-drops dosage preparation has shown stability for 12 months period in the presence of BHA and in combination of other antioxidants under refrigerated temperature. However, ear-drops dosage form was found to be stable only for a period of 6months in ambient condition. It is therefore, recommended that these dosage preparations be stored in refrigerated conditions.     

Preparation, characterization, and stability of liposome-based formulations of mitoxantrone

The preparation, characterization, and stability of lyophilized liposome-based formulation of mitoxantrone was investigated. Mitoxantrone was entrapped inside small, unilamellar liposomes composed of dioleoylphosphocholine (DOPC), cholesterol, and cardiolipin. The mean vesicle size and drug entrapment efficiency of the liposomes were ~ 150 nm and ~ 99%, respectively. Less than 1% of drug was lost and mean vesicle size remained unchanged after sterile filtration. The pre-lyophilized (pre-lyo) formulations were characterized by a differential scanning calorimetric (DSC) method. Results showed that the glass transition temperatures (Tg') increased as the molar ratios of sucrose:lipid and trehalose:lipid in the formulations were increased. The maximum Tg' of the pre-lyo formulations containing 10:1 sucrose:lipid and trehalose:lipid molar ratios were - 37°C and - 41°C, respectively. After reconstitution of the lyophilized cake of the sucrose-containing formulation, the mean vesicle size was comparable to pre-lyo liposome size. In vitro release studies showed that less than 2% of mitoxantrone was released after an extensive dialysis against phosphate buffered saline (PBS) at 37°C, indicating that the mitoxantrone was highly associated and retained inside the liposomes. Short-term stability studies of the sucrose-containing formulations revealed that the reconstituted and eight-fold diluted formulations were stable for up to 8 hours at room temperature. Long-term stability studies of lyophilized liposomal mitoxantrone showed that the lyophilized formulation was stable for up to 13 months after storage at refrigerated condition.     

Reformulation of a codeine phosphate liquid controlled-release product

Background: Ion-exchange resins have been successfully used to create drug formulations providing controlled drug release that are easy to swallow, are sufficiently stable, and have good taste-masking characteristics. The objective of the present study was to replace the ion-exchange resin in a proven delayed release codeine preparation with a new resin able to provide the beneficial properties of the original formulations without the need for Eudragit coating to comply with modern manufacturing regulations. Methods: Nine cationic exchangers with different particle meshes, form, and pore structures were optimally loaded with codeine and their respective in vitro codeine release profiles were compared using the USP XXIII paddle method. Results: The most favorable release profiles were obtained with Amberlite IR 69 F and with Dowex 50 × 8?100. The former was used to prepare the formulated drug–resin complexes as it was available in a pharmaceutically pure form. Both, the cough syrup and concentrate formulations exhibited drug release profiles equivalent to the nonformulated drug–resin complex. These profiles as well as initial free codeine levels, the purity, and the identity were moreover maintained for a storage period of at least 6 months. Conclusion: The in vitro dissolution profiles demonstrated that the use of ion exchanger is most suitable for the development of sustained release codeine formulations.     

Development of a Clinical Capsule Formulation Containing a Marginally Water Soluble Drug

A good clinical development program maximizes the clinical efficacy of a new drug product and, in addition, requires only minimal formulation changes in the transition from clinical to market image product. This study demonstrates the development design as well as the technology utilized to improve the dissolution characteristics of a marginally water soluble drug to be administered in a capsule dosage form for clinical trials. A satisfactory formulation was achieved by controlling drug particle size, selecting an appropriate diluent and incorporating a surfactant.     

Formulation, quality control and shelf life of the experimental cytostatic drug cyclopentenyl cytosine

This paper describes the formulation and quality control of an aqueous sterilized formulation of the experimental cytostatic drug cyclopentenyl cytosine (CPEC) to be used in Phase I/II clinical trials. The raw drug substance was extensively tested. A High Pressure Liquid Chromotography (HPLC) method was validated for the quality control of the formulated product. The aqueous formulation was found to be stable for at least 2 years at 2-8°C. Sterilization (15 min at 121°C) showed no influence on drug stability. The results show that CPEC can be formulated in an aqueous solution. The described HPLC method is a useful tool in the pharmaceutical quality control.     

Development of a Clinical Capsule Formulation Containing a Marginally Water Soluble Drug

Abstract

A good clinical development program maximizes the clinical efficacy of a new drug product and, in addition, requires only minimal formulation changes in the transition from clinical to market image product. This study demonstrates the development design as well as the technology utilized to improve the dissolution characteristics of a marginally water soluble drug to be administered in a capsule dosage form for clinical trials. A satisfactory formulation was achieved by controlling drug particle size, selecting an appropriate diluent and incorporating a surfactant.     

Formulation,Quality Control and Shelf Life of the Experimental Cytostatic Drug Cyclopentenyl Cytosine

ABSTRACT

This paper describes the formulation and quality control of an aqueous sterilized formulation of the experimental cytostatic drug cyclopentenyl cytosine (CPEC) to be used in Phase I/II clinical trials. The raw drug substance was extensively tested. A High Pressure Liquid Chromotography (HPLC) method was validated for the quality control of the formulated product. The aqueous formulation was found to be stable for at least 2 years at 2–8°C. Sterilization (15 min at 121°C) showed no influence on drug stability. The results show that CPEC can be formulated in an aqueous solution. The described HPLC method is a useful tool in the pharmaceutical quality control.     

Lyophilization of unit dose pharmaceutical dosage forms

A lyophilization process for a pharmaceutical unit dosage form was developed which comprised a container closed with an impermeable membrane pierced with one or more holes through which the material in the container can be lyophilized. The hole or holes in the membrane have to be sufficiently large to allow water vapor to escape but small to ensure that the material is kept within the container. Lyophilization from sealed, perforated, unit-dose package has shown to be feasible. The technique offers a novel convenient means of lyophilizing nonsterile products in their primary pack and increases the potential for the development of lyophilized formulations for nonparenteral applications.     

Physicochemical and drug delivery aspects of lipid-based liquid crystalline nanoparticles: a case study of intravenously administered propofol

Liquid crystalline nanoparticles (LCNP) formed through lipid self-assembly have a range of attractive properties as in vivo drug delivery carriers. In particular they offer: a wide solubilization spectrum, and consequently high drug payloads; effective encapsulation; stabilization and protection of sensitive drug substances. Here we present basic physicochemical features of non-lamellar LCNP systems with a focus on intravenous drug applications. This is exemplified by the formulation properties and in vivo behavior using the drug substance propofol; a well-known anesthetic agent currently used in clinical practice in the form of a stable emulsion. In order to appraise the drug delivery features of the LCNP system the current study was carried out with a marketed propofol emulsion product as reference. In this comparison the propofol-LCNP formulation shows several useful features including: higher drug-loading capacity, lower fat-load, excellent stability, modified pharmacokinetics, and an indication of increased effect duration.     

Preliminary study on the development of nanoemulsions for carbamazepine intravenous delivery: an investigation of drug polymorphic transition

Carbamazepine (CBZ) is available on the pharmaceutical market as tablets, capsules, and oral suspensions, but not as a parenteral formulation for clinical use. Parenteral emulsions are a good alternative to poorly water-soluble drugs such as CBZ. In this way, four different emulsions containing 3 mg/mL of CBZ were developed, but during a period of storage, drug crystal precipitates appeared. To investigate this phenomenon, differential scanning calorimetry, infrared spectroscopy, and light microscopy were employed. The results suggested a polymorphic transition from β form to dehydrate form, resulting in drug precipitation, although the emulsions themselves remained stable for at least three months.     

Formulation and Stability of the Antineoplastic Agent: N,H-Di-9-AcridinylHexanediamine (Nsc 1219733)

Abstract

N, N-di-9-acridinvl-l, 6-hexanediamine- (MSC 1219733) was solubilized and lyophilized for parenteral use in the form of the methanesul fonate salt. Stability studies of the drug in solution of pll 3.0, 4.5 and 7.0.and at both 25° and 70°C were carried out and the drug was stable at 25°. At 70°C sliqht degradation was observed, in solutions of pH 3.0 and 4.5, while extensive loss occurred at pH 7.0 with a half-life of 16.5 hours. The lyophilized preparation was stable for one week when reconstituted with water and diluted with 5% dextrose solution. Precipitation of the drug as the hydrochloride salt occurred when dilution was done with normal saline solution. Stability was monitored using high performance liquid chromatography.     

Photopolymerized Micelle‐Laden Hydrogels Can Simultaneously Form and Encapsulate Nanocrystals to Improve Drug Substance Solubility and Expedite Drug Product Design

Formulation technologies are critical for increasing the efficacy of drug products containing poorly soluble hydrophobic drugs, which compose roughly 70% of small molecules in commercial pipelines. Nanomedicines, such as nanocrystal formulations and amorphous solid suspensions, are effective approaches to increasing solubility. However, existing techniques require additional processing into a final dosage form, which strongly influences drug delivery and clinical performance. To enhance hydrophobic drug product efficacy and clinical throughput, a hydrogel material is developed as a sacrificial template to simultaneously form and encapsulate nanocrystals. These hydrogels contain micelles chemically bound to the hydrogel matrix, where the surfactant structure dictates the crystal size and drug loading. Therefore, nanocrystals can be produced in high yield (up to 90% drug loading, by weight) with precisely controlled sizes as small as 4 nm independently of hydrogel composition. Nanocrystals and surfactant are then released together to increase the solubility up to 70 times above bulk crystalline material. By integrating nanocrystals into a final dosage form, micelle‐laden hydrogels simplify hydrophobic drug product design.     

药用丙烯酸树脂的研究

介绍了药用丙烯酸脂的种类、结构特点、制造方法以及理论化性质。对丙烯酸树脂在工物薄膜包衣制剂中的应用概况及研究前景进行了讨论，指出该领域存在的问题和发展前景。     

电子束辐射固化环氧树脂的动态力学分析——辐射剂量、引发剂用量及热处理的影响

对电子束辐射固化的环氧树脂进行了动态力学分析。通过对不同样品凝胶含量、内耗tanδ及动态模量变化趋势的研究,得到电子束辐射剂量、引发剂用量和热处理等因素对环氧树脂辐射交联反应的影响规律。辐射剂量的增加使环氧树脂凝胶含量、玻璃化温度T_g及高温模量有所增加,但增长幅度在高辐射剂量下逐渐变小,且树脂交联体系的不均匀性随辐射剂量增大而有所增加。低剂量辐射下,环氧树脂固化物的玻璃化温度及高温模量随引发剂用量增加而增大,高辐射剂量下,引发剂的用量存在最佳值。经过热处理后辐射样品的交联程度得到提高,当热处理温度超过引发剂的热分解温度时,树脂体系中会存在因热固化反应而形成的局部交联网络。