Martin A Erickson III, RPh

A physician wrote a prescription for 8% hydroquinone cream. No antioxidants were specified. Please help!

Hydroquinone (dihydroxybenzone) is a hydroxyphenolic compound with a structure similar to melanin precursors. It prevents formation of melanosomes and causes necrosis of existing melanocytes. These properties make it useful in the treatment of skin hyperpigmentation disorders. Hydroquinone is an oxidizing agent and can turn preparations from bright white to brown in a short time; the resulting hydroquinone degradation inactivates it. Hydroquinone concentrations for hyperpigmentation disorders range from 2% to 5%; concentrations greater than that can present stability issues and also may increase the potential for carcinogenicity and dermal toxicity, among other postulated adverse effects.

A literature search revealed no formulations for hydroquinone concentrations greater than 5% in topical preparations. As noted above, hydroquinone presents a particular stability challenge to the compounding pharmacist, and the addition of antioxidants is required to make an acceptable compounded preparation. If the preparation contains greater than 5% hydroquinone, this challenge is increased greatly. Some manufacturers have developed vehicles containing high concentrations of antioxidants specifically to meet the challenges presented by readily oxidized active pharmaceutical ingredients such as hydroquinone; one example is Nourivan Antiox (Fagron). One formulation widely reported to produce positive clinical results is as follows:

Vitamin E (400 IU) contents of 4 capsules

HEB cream (O/W emulsion-vanishing), 25% 53.73 g

		Combine powders in a ceramic or Wedgwood mortar and triturate with pestle until finely divided.

		Add a small amount of water and triturate until a smooth paste forms.

		Combine and mix both the ointment and cream bases until a homogenous cream is obtained (an Unguator could be used here).

		Add a small amount of ointment and cream base to the wetted powders and triturate until smooth. Add balance of base by geometric dilution to final weight.

Stability: Studies absent, use USP 30 days (or less, if the compounded preparation turns brown). Some articles suggest 90 days because of the added antioxidants.

Mr. Erickson is director of professional affairs and director of professional services at Gallipot, a Fagron company.

Articles

A compounding question regarding 8% hydroquinone cream.

Your Compounding Questions Answered

I have a pharmacist in one of my stores looking for a promethazine gel recipe. I tried searching your website for one, but couldn’t find it. Can you please help? Thanks!

 Promethazine HCl is a phenothiazine antihistamine. It is a white to faint yellow crystalline powder that is practically odorless. It is soluble in water and practically insoluble in ether or acetone. Its water solubility is used to good advantage in compounding preparations based on pluronic lecithin organogel (PLO) gel or penetration-enhanced creams. Its solubility in water is particularly important to compounding pharmacists, because it is slowly oxidized in air, but more rapidly with moisture. This oxidative process causes inactivation, turning it blue, which makes it easy for compounders to recognize subpotent preparations. Promethazine HCl has significant anticholinergic activity and is used as an antinauseant and antihistamine as well as for pre- and postoperative sedation and adjunctive therapy in pain relief. It is well absorbed when administered orally, rectally, or by intramuscular injection, reaching peak effect within 20 minutes. Transdermal absorption is slower because of the nature of the formulations, which can mean dose titration in the clinical setting can be based on easily observed effects (sedation, relief of symptoms, and/or dry mouth). The drug can cause blood pressure changes (usually hypotension, but hypertension has been reported); if a patient exhibits photosensitivity, continued therapy may be contraindicated. In children, the drug can cause hyperexcitability and nightmares.

Several articles containing formulations and evidence of transdermal absorption are available. For a discussion of phospholipid-mediated transdermal penetration of drugs, please see previous columns or e-mail for references.

One suggested formulation is promethazine 25 mg/mL penetrating vanishing cream, calculated to make 10 g (~10 mL; useful when dispensing in unit-dose topical/oral syringes).

		Penetration-enhanced vanishing cream (eg, Pentravan [Fagron])

		Electronic balance, weigh papers or weigh boats

		Spatulas and mortar and pestle (ceramic or Wedgwood) or electronic mortar and pestle

		Calculate the required quantity of each ingredient for the preparation.

		Accurately weigh and/or measure each ingredient.

		Levigate the promethazine HCl powder with a few drops of water in the mortar, using the pestle to make a smooth paste.

		Geometrically levigate the paste in step 3 with the penetration-enhanced vanishing cream.

		Dispense it in an opaque ointment jar, an ointment tube, or light-resistant unit-dose syringes.

PLO combination gel (eg, 20% Polox gel with Lipoil 24% [Fagron]). Store at room temperature to reduce phase separation. The application area should be covered with an occlusive, nonabsorbent dressing (eg, Tegaderm [3M], Opsite [Smith & Nephew]).

This month's column addresses compounding promethazine gel.

 One of my patients cannot afford the high cost of a commercially prepared product. Do you have a formulation for it so that I can help this patient?

 The short answer is that you can help this patient, but not in this scenario as it is presented. Extemporaneous compounding has been a cornerstone of our profession’s practice since its inception. In the 1800s in the United States, food and drug manufacturing and marketing were essentially unregulated. Abuses led to the 1906 Federal Pure Food and Drug Act, which inaugurated a trend toward increasing regulation of drug manufacturing by federal agencies. The FDA is empowered by acts of Congress to promulgate regulations and enforce US Pharmacopeia standards. The Current Good Manufacturing Practices (cGMP 21CFR§§210&211) are key to pharmaceutical manufacturing regulations. In addition, the FDA promulgates informal Compliance Policy Guidance (CPG) documents for different aspects of the drug and medical device industries. CPG Section 460.200 addresses pharmacy compounding.

Pharmacists and pharmacies are licensed and inspected by the states; if a state inspection uncovers “manufacturing under the guise of compounding,” it refers the matter to the FDA, which can apply cGMP expectations to the pharmacist/pharmacy. CPG 460.200 provides a brief list of factors that the FDA uses when considering whether a pharmacy’s practices might be 

. The list is narrowly drawn but important: it provides sufficient latitude for professional judgment and usual and customary pharmacy practice.

Compounding preparations extemporaneously on lawful prescription for individual patients is within the pharmacist’s purview. When a pharmacist engages in large-scale production of preparations without prescription or evidence of pending refills, trending, etc, the practice can be regarded as manufacturing; cGMP compliance will be expected, including an approved new drug application (NDA) or abbreviated new drug application (ANDA). If a pharmacist duplicates an NDA/ANDA product without a 

 for doing so (eg, patient allergy to a component in the commercially manufactured product) or if no shortage exists (see FDA current drug shortages), the FDA may consider the act to be duplication or “manufacturing under the guise of compounding.”

I have a prescription for cidofovir cream for a pediatric patient’s wart. What vehicle and concentration should I use?

Cidofovir (Vistide, Gilead) was approved for treatment of cytomegalovirus retinitis in patients with AIDS in 1996. Its mechanism of action is suppression of cytomegalovirus replication by selective inhibition of viral DNA synthesis. It was not approved for other indications; this question concerns an off-label use. Chemically, cidofovir is an acyclic nucleoside phosphonate and therefore does not require phosphorylation by viral enzymes for its activity, as acyclovir does. It is nephrotoxic and therefore carries precautions against use in patients with impaired renal function and who are receiving therapy with other nephrotoxic drugs. Gupta M et al reported topical treatment of verrucae with cidofovir cream in 12 children (Topical cidofovir for refractory verrucae in children [published online September 26, 2012]. 

. 2013; 30[1]:131-134. doi: 10.1111/j.1525-1470.2012.01798.x. Epub 2012 Sep 26.). In this report, 7 patients exhibited partial to complete clearing of the treated verrucae when cidofovir in moisturizing cream was applied every other day at concentrations of 1% to 3%. The authors speculated that the low concentrations of cidofovir used might have led to the mediocre results. In other studies, patients have exhibited complete to partial clearing of anogenital papillomavirus lesions when treated with cidofovir.

Cidofovir is mutagenic: any preparations should be compounded using OSHA HAZMAT precautions (closed-front gown, gloves, mask, Class II biologic safety cabinet); recommended disposal of contaminated materials is high-temperature incineration.

* Eucerin (Boehringer Ingelheim); Almonderm (Fagron US).

		Using geometric dilution technique, levigate the cidofovir into a small amount of propylene glycol or the cold cream to make a paste.

		Geometrically combine the paste in (2) with the cold cream until completely mixed. (If an Unguator is used to mix the material, use disposable blades, etc.)

		Label appropriately, and dispense with precautions about contact with healthy skin.

		Keep refrigerated up to 30 days (USP<795>).

Would you be able to help us with providing a stable formulation of phenol 7.5% injectable solution for intrathecal instillation? We have a pain specialist who would like to use this for nerve blockade.

Phenol USP, or carbolic acid, (mw 94.11; d 1.071) occurs as colorless or faintly pink or yellow deliquescent crystals or more commonly as crystalline masses (fused crystals) because of its deliquescent nature. Fused crystals must be melted (preferably in a fume hood) to weigh the required quantities for compounding. Phenol USP is soluble in water, and miscible with ethanol, ether, and glycerin. It congeals at 41°C and melts at 43°C. It is incompatible with alkaline salts and nonionic surfactants. Precautions should be taken when handling phenol USP because it is corrosive and can cause toxic symptoms when absorbed through the skin or when the vapor is inhaled.

Phenol 7% in water was injected to block pain of trigeminal neuralgia. Phenol injection recently was reported to have successfully blocked refractory pain from metastatic cancer involvement of the abdominal wall (Restrepo-Garces CE, Asenjo JF, Gomez CM, et al. Subcostal transversus abdominus plane phenol injection for abdominal wall cancer pain [published online April 8, 2013]. 

It is important to compound this preparation using strict aseptic technique (see USP <797>).

		Phenol crystals...................................2.10 g

		Ethanol 95% ......................................1.00 mL

		Sterile water for injection USP .........20.00 mL

		Sterile 0.22 micron filter (stable in phenol, eg, Acrodisc syringe filter with PTFE membrane)

		Weigh 2.1 gm phenol, place into the beaker.

		Add 1.0 mL Ethanol 95% to (1) and allow phenol to dissolve.

		Add 29 mL sterile water for injection (SWFI) to (2) with stirring.

		Pass mL Ethanol 95% through the filter to wet it, then flush with 5 mL SWFI.

		Draw phenol mixture in (3) into 30 mL syringe,add filter from (4),and add 20 ga needle.

		Prepare 30 mL empty sterile vial: wipe stopper with alcohol; insert 20 ga needle as air vent.

		Inject phenol solution into vial in (6). Remove needles and seal as desired.

Precautions: Phenol is corrosive; steps 1 to 3 could be performed in a fume hood and the process moved into the cleanroom at step 4.

No claims are made as to the uses, safety, efficacy, or bioavailability of this preparation; the formulation is for information purposes only.

Mr. Erikson is director of professional affairs and director of professional services at Gallipot, a Fagron company.

Compounding Hotline: Your Compounding Questions Answered

I am interested in compounding a glycolic 30% body lotion. Also, what is the percentage for facial peels using glycolic acid crystals?

Glycolic acid (hydroxyacetic acid) is an odorless, hygroscopic crystalline substance with a melting point of 80°C. It has molecular weight 76.05 and is soluble in water, methanol, alcohol, acetone, acetic acid, and ether. The pH of various aqueous glycolic acid solutions is: 0.5% pH 2.5; 1% pH 2.33; and 10% pH 1.73. It is a constituent of sugar cane juice and can be produced commercially either by reacting NaOH with monoacetic acid or by electrolyte reduction of oxalic acid. It is a mild irritant to skin and mucous membranes. It is this irritant characteristic that makes it useful as a skin peel. A relatively stable preparation of glycolic acid in hydrophilic ointment USP with pH adjustment to 3.5 using sodium hydroxide solution has been reported. While a specific beyond-use date (BUD) was not reported because the study focused on freeze-thaw cycles, a 30 days refrigerated BUD could reasonably be assigned to this preparation.

An extemporaneously compounded facial lotion has been reported:

Glycolic acid 70% solution (aqueous).................................1.5 mL

Veegum, 5% colloidal solution............................................5.0 mL

Methylparaben..................................................................0.050 gm

Propylparaben...................................................................0.025 gm

Purified water q.s. ad......................................................100.00 mL

		Prepare the Veegum 5% colloidal solution in a graduated cylinder.

		Dissolve the methylparaben and propylparaben in 94 mL of purified water. Heat to approximately 70 to 75° C to facilitate dissolution.

		Allow the paraben solution in (2) to cool to room temperature.

		Add the glycolic acid to the solution in (3).

		Neutralize the solution in (4) with ammonium hydroxide 28% solution, adding it dropwise with stirring until the pH is about 4 to 4.5.

		Add the Veegum 5% colloid to the neutralized solution in (5) and mix thoroughly. Rinse the cylinder with the solution in (5) and return the material to the preparation.

		Bring the mixture in (6) to final volume (100.00 mL) with purified water.

		Package, label, and dispense. Consider “External Use Only,” “Caution: Irritant” (or similar). USP <795> specifies BUD 14 days, refrigerated for aqueous extemporaneous preparations.

Veegum 5% colloidal solution: Disperse 5 gm of Veegum in a small amount of water; stir vigorously to make a smooth paste. Bring to volume with purified water and continue stirring. When the colloid is allow to stand at room temperature, a smooth, creamy mixture is observed. Occasionally, a 40% solution is wanted. In these cases, note that addition of neutralizing ammonium hydroxide 28% solution to pH 4 to 4.5 will be necessary.

This month's column addresses compounding with glycolic acid.