Semisolid dosage forms are a substantial industry category, though they are sometimes overlooked in favor of oral solid dosage forms or injectables.¹ Semisolid dosage formulations include all ointments, creams, gels or jellies, pastes, rigid foams and emulsions.² These semisolids are either applied directly to the skin topically or administered via a suppository. Because of their unique composition and requirements for increased absorption, the formulation of semisolid dosage forms can be quite specialized and thus rather challenging. However, in spite of the inherent processing difficulties, the industry is innovating its approach to the manufacture of semisolid dosage formulations. Novel treatments in the category are also emerging.

The Topical Trend: Demonstrating Market Growth
A study by market research firm ReportsnReports suggests that the development of topical products will continue to increase substantially.³ The firm predicts that the topical drug delivery market will grow to $125.88 billion by 2021, with a compound annual growth rate (CAGR) of 6.4%. They forecast that this segment will expand from its $92.40 billion value in 2016, due in part to an growing population of geriatric individuals. This growth is also partially attributed to a prediction that the rate of burn-related injuries will continue to increase, as will the diagnosis of diabetes in the patient population.³ Of the total market share, North America is the most dominant region, with hospitals and private clinics predicted to be the greatest end users.³

Of the overarching semisolid category, topical drugs that are administered via the skin are expected to command the greatest value share and therefore to grow at the highest CAGR.3 This is based on the increasing prevalence of skin diseases and disorders, as well as an observed consumer demand for self-administration and the recent upsurge of product approvals centered on cutaneous drug delivery.³ The research firm also defines major players in the space, including Galderma S.A. (Switzerland), GlaxoSmithKline plc. (U.K.), Valeant Pharmaceuticals International, Inc. (Canada), Crescita Therapeutics Inc. (Canada), Medpharm (U.K.), 3M (U.S.), Bayer AG (Germany), Novartis AG (Switzerland), Janssen Global Services, LLC (U.S.) and Cipla (India).³

Judging by the imminent growth in the sector, there is no doubt that many companies are looking to enter or edge into the semisolid formulation space. The most successful organizations will need to stay on top of the manufacturing trends for semisolids, prioritizing innovation in development.

Semisolid Formulation Advancements
Among recent advances in semisolid formulation development is the elimination of greasy residue for a more tolerable drug product.2 Novel semisolids that meet this particular criterion are produced using a water-washable base, which allows for less skin irritation.² Novel creams developed with nanoparticles and microspheres are another emerging technology in the category. Of the gels, novel innovations include micro-emulsion gel, bioadhesive gel, organogel, thermosensitive sol-gel and pH-responsive complexation gel. Oleaginous ointments are also ideal for the treatment of dry or chapped skin because of their demonstrated occlusive properties.²

In addition to updated profiles for these drug products, semisolids offer an attractive way to control the mechanism for delivery, through either sustained or controlled release. For example, P407 gel is able to change the rate at which a drug is released, as can inorganic salts and PEG 400, which are regularly included in the P407 formulation. This practice is exemplified by the topical numbing agent lidocaine. P407 gel is able to sustain and prolong the duration for which lidocaine is effective at an injection site, which adds to its effectiveness as a medicinal treatment.²

The development of controlled-release semisolid formulations presents even greater challenges, but progress is being made in their manufacture. Uncharged drug substances can become controlled-release therapies with the inclusion of surfactants, which form micelles in the gel. The lipophilic interaction that occurs between the drug and the polymer and/or the micelles dictates the drug release profile, such that ultimately mixing charged drugs with oppositely charged surfactants (in specific ratios) creates a controlled-release gel formulation.⁴

Trending in Practice: Semisolid Development and Manufacture
These recent innovations in semisolids have dictated manufacturing trends. One of the most crucial processes in the manufacture of any formulation is scale-up. In order to tackle issues with scale-up, a quality-by-design (QbD) approach has to be embedded into operations.⁴

In one case study, yield stress was found to be an important influence in the mixing speed and filling temperature of a cetomacrogol ointment.⁴ The effects of the mixing and filling temperature on ointment yield stress were then developed into a definitive screening design (DSD) that allowed for the results of all variables to be easily quantified, leading to a lab- to industrial-scale design that allowed for filling up to a commercial level.⁴

Another big-picture trend in semisolid formulations and perhaps the ultimate industry priority with this dosage type relates to particle size determination. A nano or micronized particle allows for increased bioavailability and therefore increased absorption and efficacy of the drug product.

Semisolid formulations that are topically applied have to penetrate the multi-tiered skin barrier, which is a clear formulation challenge. Sizing particles in a way that is reproducible and that allows particle size distribution to be characterized as required by FDA regulations is another significant issue in semisolid development that is currently being addressed by the industry.⁵

Techniques involved in achieving particle size distribution include laser diffraction, dynamic light scattering (DLS), disc centrifugation and light microscopy. As each technique has its own specific set of advantages and disadvantages, the best option is dependent on the solution, the desired outcome for the drug and the resources available. According to a case study on light microscopy as a means to monitor particle size distribution of API present in gels in stability studies, optical microscopy was determined to be a precise method. However, this was ideal only under lab-scale or small-scale conditions, and microscopy was found to be most acceptable when preparing minimal samples.⁵

Patient Compliance
Semisolid formulations offer a unique opportunity for enhancing patient compliance.⁶ Semisolid dosing can be easier for patients, especially in contrast to injectables and even oral solid dosage forms, which routinely present issues in pediatric and geriatric populations and for those who have difficulty swallowing. Additionally, semisolid formulations can be self-administered with minimal issues. Since many semisolid formulations are akin to cosmetic formulations, they are easier for consumers to become accustomed to; dosage directions can also be less regimented. Drug manufacturers should take this into consideration when developing formulations, opting to create a more “pleasant” experience for the consumer. Patient-centric packaging is another way to leverage semisolid formulation positioning. Packaging can help form a brand image and increase consumer loyalty, as well as compliance.

A Future for Semisolids
In spite of all the progress being made in the category of semisolid formulation development and manufacturing, there is always room to update and refine all processes and drive the next innovation. As the demand for these crucial dosage forms continues to grow and formulation methods continue to advance, we will likely also observe transformations in the ways that semisolids are developed and manufactured. 

References:

1. Roth, Gil. “Semisolid Manufacturing Marketplace.” Contract Pharma. 26 Jan. 2007. Web.
2. Bora, Aditya, Sambhaji Deshmukh, Kapileswar Swain. “Recent Advances in Semisolid Dosage Form.” Int. J. Phar. Sci. Res. 5: 3594-3608 (2017)
3. Topical Drug Delivery Market Growing at a CAGR of 6.4% During 2017 to 2021. Rep. ReportsnReports. 30 Mar. 2017. Web.
4. van Heugten, Anton J.P., Herman Vromans, “Scale up of Semisolid Dosage Forms Manufacturing Based on Process Understanding: from Lab to Industrial Scale.” AAPS PharmSciTech. 19: 2330–2334 (2018).
5. Particle Size Determination in Semisolid Formulations. Rep. Particle Sciences, Inc. 2010. Web.
6. Nigel Walker. “Trends in the Topical Delivery of Dermatology Medications.” Pharma’s Almanac. 23 May 2017. Web.