Case Studies Formulation

Case Studies

Poor Solubility and Rapid Degradation in Acid

NEED:

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.

IRISYS SOLUTION:

A semi-solid matrix was developed that withstood heating to liquify for capsule filling. Capsules were enteric-coated to protect the active ingredient from degradation in acid.

OUTCOME:

Preclinical and human studies showed significant improvement in bioavailability.

Topical Peptide Gel For Wound Healing

NEED:

IriSys was commissioned to formulate a gel delivery system that was capable of delivering a precise dose of a peptide to a skin lesion, was esthetically appealing, and provided at least 12 months of stability.

IRISYS SOLUTION:

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.

OUTCOME:

IriSys manufactured a number of clinical supply batches in the range of 10 kg to 20 kg (2500 to 5000 units). The product is currently undergoing trials in Europe.

A Deliquescent Compound

NEED:

In this unique case, IriSys was presented with a compound that dissolved in its own adsorbed moisture.

IRISYS SOLUTION:

IriSys protected the drug by incorporating it into a multi-component liquid vehicle, with all work performed under nitrogen.

OUTCOME:

Formulation acceptability was confirmed using moisture uptake analyses.

Liquid Filled Hard Gelatin Capsules as a Drug Development Tool

NEED:

A client needed to move a highly insoluble product into the clinic as soon as possible.

IRISYS SOLUTION:

By evaluating a matrix of potential excipients for compatibility with the active and in vitro release, IriSys created a lipid-based dosage form for the insoluble active and improved bioavailability from 5% to 90%.

OUTCOME:

IriSys’ formulation enabled the 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.

Chemical stabilization of an IV formulation

NEED:

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 SOLUTION:

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 evaluations. Analytical methods required to quantify and monitor the appearance of low concentration degradation products were developed and validated.

OUTCOME:

The formula and manufacturing process that resulted from IriSys’ activities provided sufficient stability to allow commercialization of the new product.

Compressed Tablet Formulation to Reduce Intersubject Bioavailability Variability

NEED:

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.

IRISYS SOLUTION:

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 about15µg/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 characteristics necessary to meet all specifications, including manufacturability.

OUTCOME:

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, satisfying all of the client’s requirements.

Enteric Coated Sustained Release Pellets in Hard Gelatin Capsules

NEED:

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. IriSys was selected for the development program because of the ability to meet the aggressive timeline.

IRISYS SOLUTION:

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.

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 IIa human clinical study. Development included transfer of the formulation and manufacturing process and duplication of the in vitro release profile of the original drug product. 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.

OUTCOME:

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 produce a formulation and manufacturing process that required ingenuity and experience.

Formulation and Chemical Stabilization of a Peptide for Subcutaneous Administration

NEED:

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 SOLUTION:

IriSys initiated a multivariate formulation screening process that included evaluations of 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.

OUTCOME:

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 been achieved previously.

High Dose and Solubilization Challenges for an Intravenous Formulation

NEED:

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.

IRISYS SOLUTION:

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.

OUTCOME:

IriSys successfully eliminated the cyclodextrin from the formulation and was able to increase the drug concentration by 100%.

Liquid Filled Hard Gelatin Capsule Formulation to Reduce Intersubject Bioavailability Variability

NEED:

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.

IRISYS SOLUTION:

Preformulation studies were performed. Based on the physical and 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.

OUTCOME:

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.

Compound Prone to Deliquescence at Room Temperature

NEED:

IriSys was tasked to create a new formulation of a compound that was prone to deliquescence at room temperature. The new formulation was necessary for the client to initiate Phase I clinical trials.

IRISYS SOLUTION:

IriSys protected the drug by incorporating it into a multi-component liquid vehicle. All work was performed under nitrogen and moisture uptake was used to determine formulation acceptability.

OUTCOME:

IriSys’ new formulation met the client’s requirements and the drug product entered into Phase I clinical trials.

Water Sensitive Compound

NEED:

The client had a water-sensitive compound that required a new formulation in order to initiate clinical trials.

IRISYS SOLUTION:

IriSys developed a semi-solid matrix to stabilize the orally bioavailable oncology compound. Hydroxypropyl Methylcellulose (HPMC) V-Caps, a gelatin alternative for hygroscopic formulations, were used.

OUTCOME:

A U.S. patent was filed for a novel formulation specific to the compound. The drug product is currently in Phase I clinical trials.

Insoluble Compound

NEED:

A client specified that an insoluble compound must move into the clinic as soon as possible.

IRISYS SOLUTION:

IriSys developed a pharmaceutical formulation that provided acceptable bioavailability, stability and indication of efficacy.

OUTCOME:

The drug product is currently in advanced clinical trials.

Compound Characterized by Insolubility in Water, Poor Solubility in Oil, and Acid Lability

NEED:

A client’s compound was characterized by insolubility in water, poor solubility in oil, and acid lability. It demonstrated poor bioavailability in early clinical trials.

IRISYS SOLUTION:

IriSys developed a semi-solid matrix that was liquefied by heating to enable capsule filling. The capsules were enteric-coated to protect the active ingredient from degradation in acid.

OUTCOME:

Preclinical and human studies showed significant improvement in bioavailability.

Formulation Content Uniformity Issue due to the Low Dosage Strength

NEED:

The client’s compound was highly potent, and a low dosage was indicated. There was a uniformity issue due to the low dosage strength.

IRISYS SOLUTION:

The chemical compatibility of the compound was determined using a matrix of excipients selected from lipophilic and hydrophilic vehicles and surfactants. Candidate formulations were prepared using compatible excipients expected to provide desirable microemulsion properties.

OUTCOME:

IriSys developed a self- microemulsifying system that was used to initiate Phase III clinical trials.

Matching Orally Administered Placebo Powder Sachets to API Powder Sachets

NEED:

Irisys was challenged to formulate a placebo powder in sachets for oral administration that must be fully matched by taste, color, particle size and bulk density to the API powder in sachets.  The API is slightly sweet, off-white in color, and visually shines.  The sachets are intended to be mixed into cool beverages and the ingredients must not impact the API metabolic pathway.

IRISYS SOLUTION:

Since the API has a sweet taste, polyols were chosen as a main ingredient of the placebo.  A variety of colorants and shimmer ingredients were evaluated because the off-white color of the API made it impossible to use “as is”.  Several series of placebo were produced with different formulas.  It was determined that the difference in color between the placebo and API could be minimized by diluting the API with placebo, and no additional colorant was required.  Careful sizing of the placebo polyols was required to match the API particle size.

OUTCOME:

The final placebo formulation was fully matched to the API formulation by taste, color, particle size and bulk density.

Parenteral Formulations of PEGylated Drugs for Intravenous Administration

NEED:

PEGylation, or the covalent attachment of polyethylene glycol (PEG) polymers to therapeutic agents, is one of the most promising techniques to improve drug efficacy.  PEGylation imposes an impediment for many drug manufacturers due to the stability issues associated with development of lyophilizable, high drug loading, micelle formulations.

IRISYS SOLUTION:

IriSys was able to successfully overcome the stability challenges posed by the lyophilized drug product.  We developed a stable, lyophilizable, high drug loading, micelle formulation of the PEGylated small molecule that was appropriate for intravenous administration.

OUTCOME:

IriSys scaled-up the formulation process and enabled cGMP manufacturing of clinical trial material for our client.

Parenteral Liposomal Formulations with Multilevel Biological Performance

NEED:

IriSys was asked to develop a number of formulations consisting of nanoparticles structured and composed in ways that provide unique multilevel biological performance.

IRISYS SOLUTION:

We developed several liposomal formulations with specific, very beneficial performance attributes:

a. The nanoparticles are entrapped in the poorly flushed extracellular space of tumors.
b. Upon administration, these particles are not recognized as foreign.
c. The nanoparticles are coated with components that inhibit opsonization and phagocytosis, thereby reducing their degradation and clearance.
d. The nanocarriers were overlaid with proprietary ligands (not antibodies) constructed in a way that their lipid portion intercalates into the liposome phospholipid layer, while the more hydrophilic part (high affinity moiety) is exposed outside and available for interaction with specific receptor. This approach allows accurate targeting of the cells expressing /overexpressing particular receptors.

OUTCOME:

IriSys successfully performed optimization of pH-dependent drug release from the nanocarriers via a physicochemical approach to architectural and compositional design of the vehicle and cargo.  We scaled-up the formulation process and enabled GLP manufacturing of material for preclinical efficacy and toxicology studies.

Parenteral Liposomal Formulations of Anti-Cancer Cytotoxic Agents

NEED:

IriSys is using our expertise with nanoparticles to develop formulations of cytotoxic agents for cancer therapy.

IRISYS SOLUTION:

We have been developing nanoparticles with unique structural and composition designs that allow the targeted delivery of the cytotoxic agents to cancer cells that are over-expressing lipoprotein receptors.

OUTCOME:

This approach may also enable nanocarriers to effectively penetrate the blood-brain barrier and deliver cytotoxic agents and/or inhibitors to the cancerous cells in the brain.

Parenteral Formulations for Intraperitoneal Administration

NEED:

IriSys was requested to formulate Paclitaxel-containing, tumor-penetrating PLGA (polylactic acid, polyglycolic acid) microparticles.  Encapsulation into microparticles is beneficial because Paclitaxel is a cytotoxic chemotherapy drug that can cause tissue damage.

IRISYS SOLUTION:

We designed tumor-penetrating microparticles (TPM) that can deliver pharmacodynamically-optimized drug levels to the superficial and deep layers of peritoneal tumors.  Our unique TPM solution involved incorporation of the active antitumor agent into two different PLGA microspheres that exhibit different release rates.

OUTCOME:

IriSys optimized our dissolution method for determination of the drug release rate from TPM.  This work enabled a cGMP manufacturing process for the TPM clinical trial material.

Stable, Lyophilizable Liposomal siRNA Intraperitoneal Formulations

NEED:

The use of small interfering RNAs (siRNAs) as anticancer therapeutics is difficult due to their low transfection efficiency, poor tissue penetration, and nonspecific immune stimulation.  Their potential as anticancer therapeutics hinges on the availability of a carrier vehicle that can be administered to deliver siRNA safely and specifically to primary and metastatic tumors.

IRISYS SOLUTION:

IriSys is developing a stable, lyophilizable liposomal siRNA formulation (functional complex) for a client with a drug intended to treat malignant disease in the peritoneal cavity.  The use of intraperitoneal drug delivery is based on the theoretical potential for improved cytotoxicity when there is increased exposure of the tumor to anticancer agents.

OUTCOME:

Based on our success with development of a stable siRNA formulation, we are scaling-up the formulation process to enable cGMP manufacturing of material for initiation of clinical trials.

Long-acting Parenteral Formulations for Subcutaneous Administration

NEED:

A long-acting formulation of anti-viral or anti-cancer medication that generates sustained effective inhibitory concentrations with infrequent dosing may improve adherence to therapy.

IRISYS SOLUTION:

IriSys is using our proprietary technology to make long-lasting parenteral formulations for delivery of cytotoxic and/or antiviral drugs.  Nanosizing allows us to influence the drug release properties, while offering the advantage of higher mass packing per volume. We developed depot nano-formulations that provide up to one month sustained release of cytotoxic and/or antiviral agents.

OUTCOME:

We have scaled-up our formulation process and enabled GLP manufacturing of material for our client’s preclinical efficacy and toxicology studies.

Topical Formulations with High Electrolyte Content

NEED:

IriSys was asked to optimize the viscosity and polymer network for a topical formulation with a high electrolyte content.

IRISYS SOLUTION:

We carried out formulation development programs that consisted of optimizing the quality and dynamics of a variety of polymer networks.  This approach involved combinations of different nature polymers including polymers with high associative behavior, which provides the maximum resistance to electrolytes.  We optimized number of formulations and formulation processes.

OUTCOME:

IriSys successfully overcame stability issues associated with the loss of cream viscosity due to high electrolytes concentration, and we were able to develop stable topical formulations.  We scaled-up the formulation process and enabled cGMP manufacturing of material for clinical trials.

Topical Liposomal Formulations with Enhanced API Stability

NEED:

Liposomes are used widely for the topical treatment of dermatological diseases. The major disadvantage of using liposomes topically and vaginally lies in the liquid nature of the preparation.  IriSys was tasked with creating topical formulations of active pharmaceutical ingredients (APIs) that have enhanced permeability and stability.

IRISYS SOLUTION:

We incorporated liposomes into suitable hydrogels in order to achieve the viscosity desirable for topical application.  Various amphipathic molecules were used to form the liposomes and the method of preparation was tailored to control their size and morphology.

OUTCOME:

IriSys developed topical liposomal formulations that demonstrated enhanced stability of the active pharmaceutical ingredients.  Drug molecules were either encapsulated in the aqueous space or intercalated into the lipid bilayer; the exact location of a drug in the liposome was controlled by regulating the physicochemical characteristics and the composition of the lipids.

Modulating Drug Release for Once- and Twice-Daily Oral Dosage Forms

NEED:

An IriSys client has an immediate-release product that requires multiple daily doses.  We were tasked with converting the product into 12-hour and 24-hour tablets.

IRISYS SOLUTION:

IriSys carried out formulation development programs that consisted of modulating drug release for a variety of solid dosage forms.  A well-balanced combination of non-disintegrating insoluble fillers, a hydrophobic sustained-release matrix, binders, and water-soluble fillers was developed to create 12- and 24- hour tablets.  Curing of the tablets was found to be critical to enhance the stability of the final formulation.

OUTCOME:

We successfully optimized the curing process and overcame the stability issues associated with dissolution rate decrease.  The formulation process was scaled-up for cGMP manufacturing of clinical trial materials.

Controlled Release of Highly Water Soluble Oral Drugs

NEED:

An IriSys client is working with an active pharmaceutical ingredient (API) that is a highly water soluble and acid-sensitive compound.  We were asked to develop a solid dosage form of the API that would be suitable for oral administration.

IRISYS SOLUTION:

A tablet formulation was prepared by developing a matrix that provided a hydrophobic and swellable viscous gel barrier to the drug release. In addition, the tablets were coated with a mixture of polymers and co-polymers that imparts an acid-protective barrier.

OUTCOME:

IriSys was able to modulate the API release and formulate solid dosage forms that met our client’s requirements or oral drug delivery.

Oral Dosage Forms for Immediate Release of Highly Lipophilic Drugs

NEED:

IriSys was challenged with developing solid dosage forms of a highly lipophilic drug.  The formulation development required modulating the active pharmaceutical ingredient (API) release without compromising its solubility.

IRISYS SOLUTION:

A self-emulsifying drug delivery system (SEDDS) of a lipophilic molecule was successfully developed.  SEDDS yield fine emulsions under gentle stirring when diluted in water or physiological media with physiological motion.  A number of oils and surfactants were screened to select a few formulations that showed high drug solubility.  The formulation was optimized using anti-nucleating and suspending agents to yield complete drug release within one hour of dissolution in the physiological media.

OUTCOME:

IriSys successfully mitigated and resolved stability issues associated with the cross-linking of hard gelatin capsules and degradation of the API.  This enabled GMP manufacturing of clinical batches.