Irisys was challenged to formulate for oral administration a compound characterized by low solubility in both water and oil, which also degraded rapidly in acid. As might be expected bioavailability in preliminary trials was poor. A semi-solid matrix was developed that required heating to liquify for capsule filling. Capsules were enteric coated to protect active ingredient from degradation in acid. Dog and human studies showed significant improvement in bioavailability.
IriSys was commissioned to formulate a gel delivery system that was capable of delivering a precise dose of the peptide to the skin lesion, was esthetically appealing, and provided at least 12 months of stability. It was quickly determined that the aqueous solubility of the peptide was sufficient to provide the entire range of desired final concentrations at all levels of pH. Development began with a pH stability study. It was determined that the pH of maximum stability was in the range of 5 to 6. Subsequently, the effects of buffer species, buffer concentration, metal ions, and the presence of EDTA on stability were examined. The suitability of three common gelling agents was investigated. A combination of Methylparaben, and Propylparaben was incorporated as the preservative system, and propylene glycol was used as a processing aid to dissolve the parabens. The gelling agent that provided the best stability results was chosen for the final formula. The final packaging configuration was a 5 mL prefilled syringe. A number of clinical supply batches were manufactured in the range of 10 kg to 20 kg (2500 to 5000 units). The product is currently undergoing trials in Europe.
In this unique case, IriSys was presented with a compound that dissolved in its own adsorbed moisture. IriSys protected the drug by incorporating it into a multicomponent liquid vehicle, with all work performed under nitrogen. Moisture uptake was used to determine formulation acceptability.
A client needed to move into clinic as soon as possible. By evaluating a matrix of potential excipients for compatibility with the active and in vitro release, IriSys created a lipid based dosage form for a highly insoluble active, and improved bioavailability from 5% to 90%. IriSys’ formulation enabled client to enter the clinic, satisfy investors, obtain additional financing and soon thereafter, file an Initial Public Offering. The drug product went into Phase III in the form of a tablet. If the tablet dosage form, requiring significantly more time, had been pursued initially, essential data would have been delayed substantially, from 1 to 2 years, and as a result, investors may have responded less aggressively.
A client was interested in a new use of a well known compound for the reversal of anesthesia subsequent to dental procedures. The compound was relatively unstable in aqueous solution, and had been previously formulated as a lyophilized powder for reconstitution. The new use required a stable liquid for injection. IriSys initiated a multivariate formulation screening process that included buffer species, buffer concentration, pH, antioxidants, organic co-solvents, inert atmosphere for filling, and packaging configuration evaluation. The analytical methods required to quantify and monitor the apperance of low concentration degradation products were developed and validated. The formula and manufacturing process that resulted from this study provided sufficient stability to allow commercialization of the new product.
IriSys was requested to develop a novel tablet formulation of a poorly water soluble, high dose, steroidal analgesic. The formulation was intended to reduce inter-subject bioavailability variability. Pharmacokinetic studies indicated approximately a 10-fold variability in Cmax after administration when previously formulated as a blend with commonly used excipients and filled into capsules.
Selected preformulation studies were conducted. Forced degradation indicated the drug was not degraded by peroxide and only slightly by acid. In basic solution, the drug was very susceptible to degradation. A pH stability study showed significant degradation at pH 8. Maximum solubility in aqueous solution at lower pH values was about 15 µg/mL. Log P was determined to be 2.96. An excipient compatibility study was performed demonstrating the drug was inherently stable and highly compatible with the selected excipients. Tablet direct compression was evaluated in a composition of drug, and lactose and microcrystalline cellulose (MCC).
Dibasic calcium phosphate, dihydrate (DCP), MCC, crospovidone and magnesium stearate (MS) preparations were also studied. Subsequent experiments showed that the addition of DCP and MCC would provide a blend having the blend characteristics to meet all specifications including manufacturability. Formulations were prepared with and without bioavailability enhancing ingredients. Target fill weight and hardness met specifications. Content uniformity of 10 tablets was 98.5% with a relative standard deviation of 3.1%. Dissolution using the basket configuration at 100 RPM provided complete dissolution in 30 minutes.
IriSys was requested to expeditiously and aggressively develop for the U.S. market a product that had been tested outside the U.S. The compound had been originally formulated using spray-coated pellets encapsulated in hard gelatin capsules. The critical performance characteristics were determined by two separate in-vitro dissolution tests. One test was performed in a pH 1.2 dissolution medium, the other in a pH 6.8 dissolution medium. Protection from drug release at pH 1.2 and a specific controlled release profile at pH 6.8 were the targets. Development included transfer of the formulation and manufacturing process and duplication of the in vitro release profile of the original drug product. IriSys was among several contractors who were considered for the development program, IriSys was selected because of the ability to meet the aggressive timeline. IriSys conducted a development program to determine the feasibility of transferring the manufacturing process with the goal of enabling the generation of approximately 5 kg of clinical trial materials for a Phase 2A human clinical study. Two different equipment configurations were used in the program. First, preliminary development lots were produced using a Glatt fluid bed system to determine minimally acceptable processing conditions and maximum batch size. Then, a coating pan was used to produce development lots which after evaluation met dissolution requirements. Clinical trial materials were subsequently manufactured. Stability study testing demonstrated that the clinical trial materials were as stable as the original drug product. The aggressive timeline was met to reproduce a formulation and manufacturing process that required ingenuity and experience.
IriSys was presented with a hydrophilic peptide subject to degradation by hydrolysis for formulation development. The challenge was related to the requisite high dose and chemical stability. The formulation was to be suitable for subcutaneous administration at the highest possible drug concentration and would demonstrate two-years stability, with refrigeration if necessary. IriSys initiated a multivariate formulation screening process that included buffer species, buffer concentration, pH, and non-aqueous co-solvents. Data demonstrated the compound was more stable at pH 6 than at pH 7 and that there was no specific ion effect within the buffers that were studied. Drug concentrations as high as 200 mg/mL were achieved. Two primary degradant peaks were observed, one was a well known hydrolysis product, the other an unknown substance. The formation of these degradants was used to aid in determining which formulations were most stable. Surfactants and organic co-solvents provided a stability advantage at 40° C and 25° C however; at 5° C a precipitate was observed. IriSys was successful in achieving the high dose and chemical stability for two years without the need for refrigeration for a subcutaneous injectable product. The formulation represented a three fold increase in both drug concentration and stability over what had previously been achieved.
IriSys was challenged to develop an intravenous formulation of a neutral, poorly water soluble compound at a high dose. IriSys was requested to improve an existing cyclodextrin-drug formulation where a 30% cyclodextrin component provided the high dose concentration requirement. However, there was concern about the toxicity of the high percentage of cyclodextrin increasing potential for a regulatory approval delay. A backup formulation without cyclodextrin and based on surfactants and organic co-solvents was developed. IriSys performed a multivariate solubility and compatibility study in which the variables were co-solvent type, co-solvent concentration, surfactant type, and surfactant concentration. Binary, ternary, and quaternary systems were studied and prototype formulations prepared that were subsequently tested for solubility, pH value, osmolality, and chemical stability. During the study it became apparent that process parameters influenced solubility and stability. These were studied and modified, as appropriate. IriSys successfully eliminated the cyclodextrin from the formulation and was able to increase the drug concentration by 100%.
Case Study I: Liquid Filled Hard Gelatin Capsule Formulation to Reduce Intersubject Bioavailability VariabilityFebruary 19th, 2009
IriSys was requested to develop a hard gelatin liquid-filled capsule formulation to reduce intersubject bioavailability variability of a poorly water soluble, high dose compound. Preformulation studies were performed. Based on the physical chemical characteristics of the compound, excipient compatibility studies were conducted. A saturation solubility study in lipophilic excipients showed that there were no individual solvents that provided sufficient solubility or that were compatible with hard gelatin capsules. The study was expanded to include binary and ternary excipient systems that would provide adequate solubility and be compatible with hard gelatin capsules. A formulation was selected and studied for stability. The final formulation of the hard gelatin liquid-filled capsule was stable and over time demonstrated compatibility with the non-active components. Dissolution testing showed complete release in 30 minutes.