Liquid-filled hard-shell capsules (LFHCs) are a popular formulation for oral solid delivery of chemical drugs and nutraceuticals. Often selected for drugs with poor solubility/bioavailability, LFHCs also have applications in a number of other situations, including specific benefits during early-phase clinical development.

In Issue 28 of The Altascientist, you will find: 
•    Applications of LFHCs
•    The production process
•    The role of excipients
•    Other advantages of LFHCs
•    A case study
•    How Altasciences can help

Applications for Liquid-Filled Hard-Shell Capsules in Your Drug Development Program

The use of modern drug discovery approaches, such as combinatorial chemistry and high-throughput screening, as well as structural understanding of drug-target binding by X-ray diffraction and molecular modelling, has resulted in an increasing percentage of highly potent lead compounds.

The majority of these compounds have high-melting points and poor aqueous solubility, which directly impact their dissolution and bioavailability. In an LFHC, readily metabolized lipid-based solutions are used as liquid carriers, providing for optimized absorption of the active pharmaceutical ingredient (API).

LFHCs offer several advantages for handling these challenging APIs, including: 
•    improved safety in processing and administration of potent drugs
•    ease of administration
•    flexible application
•    abuse-resistant formulations

How Altasciences Can Help With Your Liquid-Filled Hard-Shell Capsule Formulations and Manufacturing

Altasciences has a proven track record and thorough expertise with LFHCs, having completed numerous projects over the years, for a wide range of clients. Our highly knowledgeable experts will assist you in determining the most appropriate and efficient program parameters, from batch size to excipient selection and capsule composition, color, and banding options. Our skilled operators use state-of-the-art machinery for every step of the process. We perform comprehensive process validation prior to manufacture, identifying and correcting any potential issue before it becomes a problem. We provide 100% manual inspection of the finished capsules and take pride in doing the job right the first time, every time.

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Ophthalmic medications have a particular set of challenges that can impact their speedy and successful path to market. From prototype formulation through preclinical testing, early-phase clinical and manufacturing and development, ophthalmic drug development presents with specific and unique complexities. It is best to entrust drug development to a partner with regulatory knowledge, technical expertise, and a thorough understanding of the market in this growing therapeutic area. From current reality to future trends, being at the forefront of ophthalmic drug development delivers tangible benefits to sponsors.

In Issue 27 of The Altascientist, we dive into all areas of ophthalmic drug development, including: 
•    Prototype development, formulation, and manufacturing 
•    Preparing for first-in-human studies 
•    Species and strain selection parameters 
•    Routes of administration 
•    Specialized ocular assessments and equipment 
•    bioanalysis
•    Phase I clinical research
•    Phase II to commercialization

Three case studies are also included!

Navigating the Complexities of Ophthalmic Drug Development

The global market for ophthalmic drugs was valued at USD 36.7 billion in 2020, according to Grandview Research. The compound annual growth rate (CAGR) is expected to be 6.4% from 2021 to 2028. The acceleration in market growth is influenced by increasing awareness of eye-related diseases and advancements in related technology. The aging of the population, as well as the impact of COVID-19 ocular involvement, are also contributing factors. Certain ocular diseases are quite rare, whereas others, such as cataracts, age-related macular degeneration (AMD), and glaucoma, are very common, especially in the aging population.

Drug development in the ocular space has specific challenges. The eye is a multi-faceted organism and has many barriers to drug delivery. Formulation and delivery options must be expertly planned and developed to overcome those barriers and ensure that the maximum bioavailability is achieved without negatively impacting vision or the physical structure of the eye. Planning of preclinical studies must consider the appropriate animal species for the route of administration and therapeutic area of the investigational drug. Some species are more appropriate for certain routes of administration, while others have relevant retinal mutations that can be leveraged in ocular development.

Clinical trials need to be carefully designed by knowledgeable specialists with significant ophthalmic experience. The delicate nature of the eye and the importance of subject safety are key considerations. Just as importantly, the bioanalysis of trial samples necessitates the use of bioanalytical techniques created especially for the often uncommon and frequently fragile matrices involved. Finally, understanding the regulatory environment and related guidances, as well as proactive and appropriate discussions with relevant agencies when warranted, are critical components of the pathway and can help ensure a seamless experience.

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A crucial feature of drug development is bioavailability, defined as “the ability of a drug to be absorbed and used by the body.” For a drug to be bioavailable, it must first be soluble, meaning able to be dissolved, especially in water. Many drugs on the market today are poorly water soluble, and patent extensions or 505(b)(2) new patents become possible for formulation improvements delivered via nanomilling.

In Issue 22 of The Altascientist, we review:

• solubility classifications
• overcoming solubility challenges
• the benefits of nanomilling  
• how nanomilling works
• maximizing formulation

Case study included!

Overcoming Solubility Challenges With Nanomilling

Promising therapeutic molecules, even if classified as poorly soluble, can be developed successfully. There are multiple technologies available to increase the solubility and oral bioavailability of poorly soluble molecules being developed as active pharmaceutical ingredients  (APIs) by reducing their particle size.

Nanomilling is a universal technique that can be applied to almost any API with water solubility below 200 μg/mL. It is a very adaptable drug delivery platform suitable for oral, injectable, inhalable, and buccal applications, for which fine drug particulates are especially desired in formulations.

Nanomilling is a unit operation where mechanical energy is applied to physically break down coarse particles to finer ones. It has wide commercial and industrial applications, as every drug can be ground to finer particles, whether aqueous or non-aqueous soluble. Decreasing the size of the API molecule increases the size of the specific surface area; the larger surface area allows for greater contact with water, increasing the API’s dissolution rate and bioavailability.

The Benefits of Nanomilling

Benefits of particle size reduction for the parenteral route include small dose volumes (resulting from high drug loading) and avoidance of harsh solvents and/or extreme pH conditions. Advantages for the pulmonary route include the ability to use inhalers intended for solutions, as well as the ability to produce spray-dried powders whose particle sizes are optimized for deep lung delivery.

Other advantages include reduced fed/fasted variability in both liquid and solid dosage forms, faster onset of therapeutic action, low excipient side effects, and the ability to run continuously.

How Altasciences Can Help Improve Your Drug’s Bioavailability With Nanomilling

Nanomilling is a highly complex process requiring a unique level of CDMO expertise that can only be gained through extensive experience with developing a broad range of APIs.

At Altasciences, we can take your API from formulation to commercialization. We have the necessary procedures, equipment, and experience to work with any formulation. Our highly skilled teams work with the latest equipment, including the NETZSCH DeltaVita® 15-300 mill, that with our wet milling options can reduce particles to nanometer size, fill vials in a range of sizes (from 0.3 ml to 500 ml), and package them.

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