Pharma Focus Asia

Enabling the delivery of the poorly soluble and unstable drugs to the site of action

Yogeshwar Bachhav, Founder and Director, Adex Pharma consultancy Services

Effective delivery of the difficult to solubilise and labile (unstable) drugs has remained a great challenge for a formulation scientist. Low solubility of the drug leads to incomplete dissolution in the GI tract and hence lower bioavailability. Current drug discovery pipeline is composed of almost 60-70 per cent of the molecules indicating low solubility and thereby lower bioavailability. Formulation technologies such as amorphous solid dispersions, micronization, nanosuspensions, lipid-based delivery systems (SMEDDs/ SEDDS), mesoporous silica particles are extensively studied to enhance the in vivo dissolution rate and bioavailability in the clinics. The optimisation of the formulation and scale up is a complex task and must be designed meticulously. Drugs which are unstable in the GI tract (drugs sensitive to acidic or basic pH) and sensitive to hydrolytic/oxidative degradation can be delivered at the target site if formulated in an optimum manner. Stabilising excipients such as antioxidants, chelating agents, complexing agents (cyclodextrins) and pH modifiers are reported to stabilise the drug in the final formulation (with the anticipated shelf life) and also during in vivo passage Formulation technologies also play an important role to extend the life cycle management of the marketed drugs and to obtain additional IP protection of the drugs under development.

1. How do formulation technologies contribute to the development of novel drug delivery systems?

The drug discovery pipeline is composed of around 60-70 per cent molecules with low solubility (compounds from the BCS class II and IV), which leads to low bioavailability following oral administration. Significant efforts are needed to improve the solubility/dissolution rate of these compounds and formulation technologies are of immense help for this purpose.

Techniques such as spray drying and hot melt extrusion are used to develop novel drug delivery systems such as amorphous solid dispersions (ASDs) which are reported to improve the bioavailability of the poorly soluble drugs. Nanosuspension is one of the novel drug delivery systems produced using techniques like media milling (ball milling), high pressure homogenisation to increase the bioavailability of difficult to solubilize drugs. Advanced drug delivery systems such as mesoporous silica particles are produced using the solvent evaporation technique where the objective is to entrap amorphous form of the molecules within the mesopores of silica particles to improve the bioavailability. Lipid-based systems such intralipid emulsions are produced using high pressure homogenization.

Thus, successful development and scale up of novel drug delivery systems necessitates use of formulation technologies.

2. What are some challenges or limitations associated with formulation technologies and how can they be overcome?

Formulation technologies used to produce novel drug delivery systems or enabled formulation have their advantages and disadvantages. Some of the major limitations of these techniques are the operational cost, impact of the timelines for the development, scale up challenges, degradation of the drug and limited know-how.

Selection of the given formulation technology to develop desired novel drug delivery systems is driven by suitability with the target drug candidate/formulation. If any technique has significant impact on the timelines for development, efforts should be made to explore an alternative which can speed up the overall process. For example, the lyophilization process often needs longer cycle times compared to liquid  fill and finish operations in the case of parenteral formulations. This could impact both the timelines, operational cost as well stability of the drug under processing conditions (for drugs with instability issues). Hence, in this case the later option is better suited if the formulation is stable in liquid over long time storage.

Similarly, for heat unstable or labile molecules, selection of the formulation technology is driven by the stability of the drug candidate under the processing conditions. Drug substances with strong tendency for aggregation may not be suited for jet mill technology to produce micronized material, in this case solvent precipitation technique is better suited to obtain the  size reduction.

In summary, the selection of the formulation technique will be based on the above-mentioned limitations and alternative solutions at disposal; it could vary on a case-to-case basis.

3. How does the choice of formulation technology impact the stability and shelf-life of a product?

Often the formulation technologies involve use of extreme conditions such as use of organic solvents, high pressure, or high temperature.  There are fair chances that the molecules which are sensitive to these conditions undergo degradation. For example, a drug sensitive to thermal degradation will not be suited for the hot melt extrusion process used to produce solid dispersion. Similarly, the spray drying process cannot be used for the drugs which may undergo degradation in the presence of organic solvents at high temperature.

Drugs sensitive to oxidative degradation can not be subjected to high pressure homogenization used to produce intralipid emulsions.

Hence, due consideration must be paid for the selection of the technology to produce a formulation to rule out any degradation to obtain a stable product with the desired shelf life. Any undesired formation of the impurities/degradation products will severely compromise the safety and efficacy of the drug product in clinical use.

4. Can you discuss the role of formulation technologies in enhancing the bioavailability of poorly soluble drugs?

Poorly soluble drugs significantly limit the bioavailability upon oral administration. Significant advances have been made to improve the bioavailability of  the difficult to solubilise compound with the effective use of different formulation technologies.

Various principles are explored to improve the solubilisation such as converting the crystalline form of drug into an amorphous form with increased dissolution rate, reduction in the particle size to improve overall surface area which leads to increase in dissolution rate, solubilisation of the drug into the lipid-based vehicles to improve in vivo dissolution, complexation of the drug to cyclodextrins which encapsulate the hydrophobic part of the drug molecule in order to effectuate solubilisation.

The following technologies can be used to develop new drug delivery systems to improve bioavailability.

• Hot melt extrusion: Amorphous solid dispersion
• Spray drying: Amorphous solid dispersion.
• Jet milling: Micronisation
• Media milling: Nanosuspension
• High pressure homogenization: nanosuspension and intralipid emulsion
• Anti-solvent precipitation: Nanosuspension
• Solvent evaporation: Mesoporous silica particles
• Complexation: Cyclodextrin complexes

5. What are some emerging trends or advancements in formulation technologies?

The following areas have reported significant advancements in formulation technologies.

Inhalation products (Pills, capsules): Products to be administered by inhalation route represent a big business opportunity. Patients suffering from asthma and other respiratory diseases would not mind paying good money for an efficient inhalable product, as the faster onset of action and reduced incidence of side-effects is highly desired. For each kind of inhalation device, the formulation challenges are different. Droplet size and viscosity of the solution are critical in the case of the metered dose inhaler, When the dry powder inhaler is used, significant optimisation of particle engineering is needed with respect to the particle size, flow properties and polymorphic forms.

Modified/sustained release dosage form: The need for modified release dosage forms is increasing at the same speed at which formulations are developed. For drugs unstable  in the stomach or with potential of gastric irritation, intestinal release is highly desired to avoid drug degradation and adverse events. The intestinal release technology can be explored  for both new chemical entities as well as for life cycle management of the approved drugs. Patient compliance (due to reduction in the number of pills taken per day) and low incidence of the side-effects (due to low peak plasma concentrations) are two factors driving  demand to develop modified/sustained release dosage forms. Many pharma companies are exploring this option of modified release dosage forms to extend patent periods and thereby maintain market share. Formulation technologies such as multi-particulate formulations, pelletization are again of significant importance to develop the modified release dosage forms.

Combination products: The market for fixed dose combinations of products which often contain two or more drugs is growing and its leading pharmaceutical companies to explore this option to develop new formulations for the existing drugs. Reduction in the number of pills taken every day is a preferred option by physicians and patients to improve patient compliance. Combining  two or more drugs in a combination product is a significant challenge. And to ensure the stability of the respective ingredients in the formulation to obtain the desired PK/PD response may necessitate the use of the advanced  techniques such as layering, pelletization or mini tabulation of the individual drugs.

Paediatric medications formulations: It should be noted that paediatric populations have different needs compared to adults such as smaller doses, inability to swallow tablets or capsules, and adaptation of the dosage form to child weight. Hence, liquid dosage forms are easy to administer compared to the tablets and can also be adjusted as per age, body weight and pathological condition. Taste masking is advantageous while using tablets and capsules compared to liquid dosage forms. Longer shelf life of paediatric formulation can be ensured using dry syrups in bottles.

Abuse deterrents: Regulatory authorities are advising pharmaceutical companies developing certain types of products such as opioids to explore the technologies which will prevent them being abused. To address this concern, various technologies are explored to prevent tablets from being crushed, melted, or manipulated which could facilitate the API release. The effectiveness  of the technology depends on the drug, as one of the technologies prevents dissolution of tablets in alcohol while others prevent the release in response to physical manipulation.

6. How do formulation technologies support the development of personalised medicine or customised drug formulations?

Lastly the personalised medicine concept has been proven to play an important role in the clinics. Personalised medicine modifies conventional dosage forms as per the patient’s needs. And this improved concept allows the individual patient to effectuate the best treatment options and decrease adverse effects.

The goal of personalised medicine is to tailor the drug administration to an individual while considering the pathophysiology, response to drug and  genetic profile of the patient. Among the several emerging technologies which help to shift from the conventional dosage to personalised medicine, 3D printing is gaining attention. 3D printing deals with the creation of three-dimensional objects (through the formation of layer upon layer) using computer software. This technology can be used to produce a variety of drug delivery systems differing in shape, release kinetics and combination of the ingredients. In future, this technology can be used to dispense the medications based on the individual needs.

7. How does the stability of drugs impact their formulation and delivery?

Drugs sensitive to pH dependent, oxidative, hydrolytic degradation or thermal degradation will limit the choice of the delivery system. Dry powder systems are better suited compared to a liquid formulation for a drug sensitive to hydrolytic degradation and intended for parenteral administration; for oral administration a tablet or capsule formulation is preferred. Use of antioxidants is recommended for the drugs sensitive to oxidative degradation. Photoprotective primary packaging can be a preferred option for the drugs prone to photodegradation.

Also, stability of the drug can impact the choice of the route of administration drugs sensitive to acidic pH of the stomach are often delivered via parenteral route to avoid extensive gastric degradation. Large molecules are sensitive to acid catalysed degradation and hence mostly delivered via the parenteral route. Topical route of administration is often explored for drugs sensitive to degradation via oral route.

8. What are some common issues encountered when formulating and delivering unstable drugs, and how can they be addressed?

The most common problem occurring during the formulation development and storage of the unstable drugs is the degradation of the drug on its own  or in contact with the excipients and/or primary packaging components. This leads to the formation of drug degradation products which may produce toxic effects.

This issue can be addressed by conducting the forced degradation studies for a drug candidate alone and in contact with the excipients and primary packaging material. The outcome of these studies will help understand the possible drug degradation mechanism and selection of the appropriate excipients such antioxidants, pH-modifiers, chelating agents, complexing agents. Use of the protective primary packaging materials (e.g., packaging materials with moisture barrier and photoprotective packaging).

9. Can you explain how formulation technologies help protect and stabilise unstable drugs during storage and administration?

As addressed before, the first step would be to understand the degradation kinetics of the drug and possible factors leading to its degradation. Based on this information, the choice of formulation technology can be made which may help to protect the drug during administration and storage. The choice could vary depending on the susceptibility of the  drug candidate to the different stress factors such as temperature, water content/atmospheric moisture, pH of the microenvironment, photolytic stress or contact with the primary packaging etc.

For drugs prone to hydrolytic degradation and only stable at acidic pH, intended preferred route will be parenteral administration and lyophilised formulation will be best suited.

10. How do formulation technologies impact the release profile of soluble and unstable drugs in controlled or sustainedrelease formulations?

Controlled or sustained release formulations are desired for the drugs with short life. In this case, rate controlling polymers such as polymethacrylates, cellulosic polymers are used to control the dissolution rate of the drug during the GI transit. Focus is to obtain the delayed or controlled release over 12-to-24 hours depending on the expected duration of treatment. Conventional tableting techniques may be explored to produce the sustained release dosage forms using these polymers.

Pelletisation is one of the techniques explored to produce a controlled release formulation owing the ideal low surface area-to-volume ratio that provides an ideal shape for the application of film coatings. Use of sustained release dosage forms is very important in terms of patient compliance, reduction of see-saw fluctuations related to exposure of drug, reduction of total dose of the drug, and improved overall efficacy of the treatment. Acid labile drugs (drugs which are unstable in the acidic medium of stomach) can be delivered using the enteric coating. The oral solid dosage form in this case uses a polymer which is insoluble in the acidic medium and will only release the drug at the intestinal pH. Similarly, the drugs which are not stable at intestinal pH can be delivered effectively using the gastroretentive dosage forms. For example, osmotic tablets (pump) are evaluated to develop gastroretentive dosage form of Diltiazem Hydrochloride.

11. Any other comments?

The pharmaceutical industry is witnessing the shift from small molecules to large molecules (proteins, antibodies, and vaccines). These molecules are produced using biological systems and that makes overall formulation development a complex process. Large molecules are administered by parenteral route due to the poor stability and absorption following oral route. Hence, significant efforts are needed to develop painless delivery of the biologicals to improve the patience compliance. Also, poor stability of the large molecules in the formulation is a major challenge necessitating cold chain supply, hence there is a need to come up with the formulation technologies which can stabilise these molecules allowing room temperature storage and shipment.

--Issue 53--

Author Bio

Yogeshwar Bachhav

Yogeshwar Bachhav is Pharmacist by training and PhD in Advanced drug delivery systems from ICT, Mumbai (India). He has around 16 years of Post PhD experience in Europe in the field of Pharmaceutical Development of investigational drugs. Currently he is working as Director (Consultant) at AiCuris Anti-infective Cures AG Germany and responsible for Pharmaceutical Development of investigational drugs in the domain of innovative antiviral and antibacterial drugs. He has also started a consultancy firm called Adex Pharma which deals with solving complex issues in the pharmaceutical development of new and approved drugs since 2016.

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