by PCCA

In numerous discussions with compounders recently, the experts on our Clinical Services team have found that there is confusion around some of the different types of progesterone, specifically when to use a micronized progesterone powder and when to use a wettable progesterone powder. To help you determine the best choice, here are some considerations for choosing which progesterone to use.

Micronized or Wettable Progesterone?
For most compounded medications, our Clinical Services and Formulation Development teams recommend that compounders use a micronized progesterone. They specifically prefer our exclusive, USP-grade Special Micronized Progesterone, which has a particle size of 90% less than 5 μm and 100% less than 10 μm to promote better bioavailability. The USP monograph for progesterone does not specify micronization standards,¹ but ours meets or exceeds the monograph criteria and leads the industry in particle size, going beyond what is required.

However, we also offer a USP-grade wettable progesterone for certain situations. To further clarify when compounders should use which type of progesterone, we asked Melissa Merrell Rhoads, PharmD, Director of Formulation Development at PCCA. “Our Special Micronized Progesterone is versatile and can be used in almost any dosage form, from topical creams, oral capsules and troches to rapid dissolve tablets, suppositories and more,” she said. “We typically only recommend the use of wettable progesterone when a troche or suppository is needed at concentrations above 200 mg.” This is because wettable progesterone incorporates more easily into melted bases at these higher concentrations. “However, progesterone troches with concentrations above 100 mg are very bitter, so palatability and patient compliance could be an issue,” Melissa said. “There are really very few reasons not to use our Special Micronized Progesterone — it’s very high quality and less expensive than our wettable version.”

Some compounders have also shared with us that they believed wettable progesterone is less bitter than micronized progesterone, which is a consideration for troches and other dosage forms in which the patient’s taste is a factor. However, our clinical and formulations experts maintain that there is no difference in the bitterness of micronized and wettable progesterone powders. As Melissa indicated above, it is the amount of progesterone, regardless of the type, that will affect the bitterness of a compounded medication.

What Makes It Wettable?
If you do need to use a wettable progesterone, it’s also important to consider what makes it wettable. There are various options available in the compounding industry, but not all of them are USP grade. Even some that are labeled as USP grade contain additives, such as surfactants like sodium lauryl sulfate, that make them wettable. These are often listed on the chemical’s certificate of analysis or safety data sheet. Some USP drug substance monographs explicitly allow additives, and some do not. Thyroid USP’s monograph, for instance, states that “it may contain a suitable diluent such as lactose, sodium chloride, starch, sucrose, or dextrose.”² On the other hand, the USP monograph for progesterone does not explicitly mention an additive.¹ This calls into question whether progesterone powders with additives can, in fact, be USP grade.

Matt Martin, PharmD, PCCA Clinical Compounding Pharmacist, finds this concerning. He points out two sections in the General Notices and Requirements of the United States Pharmacopeia and National Formulary: Section 3.20, Indicating Conformance, and Section 5.20, Added Substances, Excipients, and Ingredients.

Section 3.20 states that “when a drug product, drug substance, compounded preparation, or excipient fails to comply with the identity prescribed in USP or NF or contains an added substance that interferes with the prescribed tests and procedures, the article shall be designated by a name that is clearly distinguishing and differentiating from any name recognized in USP or NF.”³ When considering this passage in relation to wettable progesterone, Matt wonders, “How does a chemical comply with the identity of the USP monograph when it has another chemical that is not discussed in the monograph?”

Section 5.20 states, “Added substances are presumed to be unsuitable for inclusion in an official article and therefore prohibited, if their presence impairs the bioavailability, therapeutic efficacy, or safety of the official article; or they interfere with the assays and tests prescribed for determining compliance with the compendial standards (see section 3.20 Indicating Conformance).”³ Even though this doesn’t rule out additives unless they impair bioavailability, therapeutic efficacy or safety, or they interfere with determining compendial compliance, Matt again raises questions. “How can a company supplying the progesterone with an additive prove that the additive does not create any of these issues?” he says. “Do they have data that can prove this?”

Fortunately, our USP-grade wettable progesterone does not contain additives, but instead is rendered wettable through its manufacturing process. PCCA customers will not find any additives listed on our wettable progesterone certificates of analysis or safety data sheets for this reason.

Soy Source? Not to Worry
Aside from questions about using micronized or wettable progesterone, compounders have also voiced concerns about the fact that some bioidentical hormones — our wettable progesterone included — are derived from soy sources. They are rightly concerned because some patients have allergies or sensitivities to soy. However, even though we list the soy origin of some of our bioidentical hormones, they do not actually contain soy allergen. This is due to the chemical manufacturing process. While the manufacturers may use soy as the starting material to begin chemical synthesis of the bioidentical hormones, the processing steps involved mean that the end product is far removed from the starting material, so much so that they have no detectible soy content.

To prove this, we submitted some of our hormones to an independent lab for allergy testing. (You can see which ones here.) The lab tested specifically for soy content, and the controlled tests found no soy-based allergens with a limit of detection of 2.5 parts per million, or 0.00025%. This means that it would be incredibly unlikely for one of these hormones to cause an issue for a patient with a soy allergy.

Gus Bassani, PharmD, PCCA’s Chief Scientific Officer, wasn’t surprised with the results. “With the pure, pharmaceutical-grade drug substances that we carry, the expectation was that there would not be any soy-based impurity present, despite the fact that soy sterols were used as the starting material to begin chemical synthesis to the bioidentical sex hormones,” he said.

The Bottom Line
With so many choices for chemicals in the pharmacy compounding industry, many of which claim to be of the highest quality, it can be difficult at times to determine which ones are the best choice for your patients. When it comes to progesterone, our experts recommend a USP-grade, micronized progesterone in most cases — specifically Special Micronized Progesterone because of its unparalleled particle size, and because it, like all of our active pharmaceutical ingredients, goes above and beyond minimum requirements and meets The PCCA Standard™. If you need to compound with a wettable progesterone, such as when incorporating it into a melted base at a high concentration, we recommend using one that is USP grade and that does not contain additives. And even if we indicate that one of our bioidentical hormones has a soy source, it is very unlikely that a patient with a soy allergy or sensitivity will have issues with it.

As always, if PCCA members with Clinical Services access have questions about compounding with progesterone, they can contact our clinical compounding pharmacists at 800.331.2498.
 

References
1.    United States Pharmacopeial Convention. (2019). Progesterone. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.
2.    United States Pharmacopeial Convention. (2019). Thyroid. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.
3.    United States Pharmacopeial Convention. (2019). General notices and requirements. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The references cited did not necessarily evaluate PCCA products or formulas included in these statements. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.