Stuart R. Gallant, MD, PhD

In today’s post, we will look at subcutaneous suspensions as a way of meeting difficult drug delivery challenges.  To decide whether a subcutaneous suspension might be appropriate for a small molecule drug product, three screening questions must be considered (see Venn diagram above):

1. Is the active ingredient degraded in the gut?  If not, then a tablet, capsule, or liquid such as a syrup may be the best option.  If the active is degraded in the gut, then parenteral delivery is required.
2. Is the active ingredient degraded by moisture during storage?  If not, a sterile liquid for parenteral delivery is a good option.  However, if water is a problem, then a lyophilized product for parenteral delivery will be needed to protect the drug during storage.
3. Is the active ingredient poorly soluble?  If not, again a sterile liquid for parenteral delivery may be the best bet.  In contrast, a subcutaneous suspension will allow the dose of a poorly soluble small molecule to be maximized.

How Do Subcutaneous Suspensions Perform Pharmacokinetically?

Before discussing manufacturing strategies, let’s consider how this dosage form performs pharmacokinetically?  Sigfridsson and coworkers compared different dosage forms of griseofulvin in mice [1].  The PK curves of griseofulvin administered intravenously and as micro-suspension (particle size distribution between 1 micron and 10 micron with mean particle size of 4 micron) are seen below [2]:

As can be seen in the figure, administration of a subcutaneous suspension significantly lengthens the plasma half-life of the dose, compared to IV administration.  More importantly, use of a subcutaneous suspension dramatically increases the dose that can be delivered in a given volume.  Griseofulvin has a solubility of approximately 10 micrograms per ml.  The microparticulate subcutaneous suspension shown above was delivered at 1 mg/ml—a 100x increase.  This is relatively common—that a suspension formulation increases the deliverable dose of a poorly soluble drug by two orders of magnitude.

Common Manufacturing Techniques

Sterile parenteral suspensions consist of a set of common chemical components in appropriate proportions:

• Active Pharmaceutical Ingredient:  The API exists in the drug product as micro or nano particles.  To maintain consistent pharmacokinetic and pharmacodynamic performance from manufacturing lot to manufacturing lot, the API particles must maintain a consistent size distribution.  Formulation agents are added to preserve the sized distribution and prevent settling, flocculation, aggregation or other adverse events.
• Stabilizers:  The “magic” of the formulation is the addition of stabilizers which protect the API particle size distribution.  Common stabilizers include pharmaceutical detergents (for example nonionic block copolymers), cellulose derivatives, and phospholipids such as lecithin.
• Bulking Agents:  Sugars (such as mannitol and sucrose) are added to the formulation to ensure a uniform and easily reconstituted lyophilization cake if the drug product is to be freeze dried.
• Buffers:  To increase stability by preventing pH drift over time, pharmaceutical buffers such as histidine are included in the formulation.

The drug product may be manufactured in one of three ways:

1. Use of Sterile Milled API:  This method is often used in academic studies.  Unmilled API is typically produced by crystallization.  The API is then milled and combined with stabilizing agents.  The challenge of this method is maintaining sterility during the milling and the compounding.  There are GMP pharmaceutical manufacturers who can do this kind of work at commercial scale, but they are limited in number and manufacturing costs are high.  So, use of this technique can create significant supply chain problems in drug product manufacture.
2. Crystallization:  This method dissolves the active ingredient in an organic-rich solution.  Addition of a counter solvent reduces API solubility, leading to crystallization.  This method of crystal formation may be combined with recirculation through a microfluidizer to control the particle size distribution.  Crystallization is a relatively easy unit operation to scale up, but large scale sterile microfluidizers are uncommon in the contract manufacturing sector.  Again, careful consideration to the robustness of the supply chain should be factored into the decision to proceed with this method.
3. Lyophilization:  Lyophilization offers a third and relatively manufacturing friendly method of producing subcutaneous suspensions.  In this method, a combination of aqueous and organic solvents is used to dissolve the API and the formulation ingredients.  This solution is sterile filtered and filled into vials, cartridges, or other primary packaging.  Lyophilization with the correct proportions of formulation agents results in a superficially uniform lyocake—however the cake contains micro non-uniformities.  Reconstitution results in a microsuspension of unform repeatable particle size distribution—a blueberry muffin in which the blueberries are microparticles of API and the muffin is carbohydrate, lipid, and detergent.  Reconstitution with water yields an injectable suspension.

Appearance of Subcutaneous Suspension

To see what a subcutaneous suspension “blueberry muffin” prepared by lyophilization looks like, see the figures below [3]:

On the left, is the sterile lyophilization cake contained in a parenteral vial.  On the right is the reconstitute drug product ready to be drawn up and injected subcutaneously.

Conclusions

Parenteral delivery of an adequate dose of a poorly soluble small molecule can be a challenge.  Use of lyophilization technology to create a subcutaneous suspension allows the dose to be boosted by a factor of approximately 100x over what would be possible in a solution for injection.  This approach uses technology available at many contract manufacturers, simplifying the supply chain and offering an additional tool in formulation development scientists toolbox.

[1] Sigfridsson, K., et al.  “Sustained release and improved bioavailability in mice after subcutaneous administration of griseofulvin as nano- and microcrystals,” International Journal of Pharmaceutics 566 (2019) 565–572.

[2] Note:  Sigfridsson and coworkers delivered an IV of nanocrystals, rather than at solution.  This is not relevant to the discussion of the discussion of the pharmacokinetics of IV delivery vs subcutaneous suspension because IV nanocrystals perform essentially the same as an IV solution from the point of view of plasma half-life.  Interested readers are invited to dig into [1] for more details.

[3] WIPO.  “WO2022072820 – LYOPHILIZED COMPOSITION COMPRISING (S)-ISOPROPYL 2-((S)-2-ACETAMIDO-3-(1H-INDOL-3-YL)PROPANAMIDO)-6-DIAZO-5- OXOHEXANOATE FOR SUBCUTANEOUS ADMINISTRATION AND THE USE THEREOF.”

Disclaimer:  PharmaTopo^TM provides commentary on topics related to drugs.  The content on this website does not constitute technical, medical, legal, or financial advice.  Consult an appropriately skilled professional, such as an engineer, doctor, lawyer, or investment counselor, prior to undertaking any action related to the topics discussed on PharmaTopo.com.