Ascorbic acid

Ascorbic acid, commonly known as vitamin C, is an essential water-soluble vitamin that has several clinical applications. It is US Food and Drug Administration (FDA)-approved only as a dietary supplement to prevent and treat scurvy and to enhance the absorption of nonheme iron, the iron contained in food.1 Ascorbic acid has been the primary focus of numerous studies on, for example, the prevention of the common cold and risk reduction of developing certain cancers.

In the hospital setting, high-dose ascorbic acid is used on burn units to reduce the need for resuscitation fluids and to promote wound healing. Tanaka et al,2 in a randomized, prospective study, demonstrated that severely burned patients on high-dose ascorbic acid therapy (infused at on mg/kg/hr) only required 3 mL/kg of fluids compared with the control group, which required 5.5 mL/kg (P

The recommended dose for patients with severe burns, in both adult and pediatric patients, is 200 to 500 mg/day until healing has occurred or grafting operations are complete.1,5 Ascorbic acid can be given intravenously, intramuscularly or orally. It is commercially available in several dosage forms: timed-release capsules, tablets (regular, timed-release or chewable), crystals, injection, lozenges, oral liquids, powder, oral solutions and oral syrups.

A clinical pharmacist who was reviewing orders in a pediatric burn unit noted that a patient was receiving oral high-dose ascorbic acid therapy. The child could not swallow tablets and was receiving Cecon, which is an oral liquid dosage form. Since some excipients can be a concern, especially in the pediatric population, the pharmacist called the manufacturer, Abbott Laboratories (Montreal, Canada), to And out the propylene glycol content of Cecon.

Propylene glycol, commonly used as a food and drug additive, has been demonstrated in numerous case reports and studies6-10 to increase the risk of serum hyperosmolality with a marked osmolar gap, lactic acidosis, seizures and cardiac arrhythmias when the patients received high-dose, long-term administration of propylene glycol. Concern about propylene glycol toxicity prompted the World Health Organization (WHO) to establish a maximum daily intake limit of 25 mg/kg/day, although there is no known toxicity dose.11 The calculated propylene glycol dose that this particular patient was receiving with the Cecon was 280 mg/kg/day, which is ten times the maximum daily intake recommended of 25 mg/kg/day.6

As the hospital's compounding pharmacist, I became involved when the clinical pharmacist called to ask how much 1 milliliter of propylene glycol weighs. This was an odd question, and I inquired as to the reason for the requested information. The propylene glycol content of Cecon was reported in millilitcrs, and the clinical pharmacist needed a conversion to milligrams in order to determine the propylene glycol dose.

An inquiry was sent to the Drug Information Center (DIC) to determine if there was a commercially available oral liquid form of ascorbic acid with a lower propylene glycol content or a propylene glycol-free product that was available through our wholesaler. All of the commercial products researched contained too much propylene glycol for the high-dose therapy, or the propylene glycol content was unknown (Table 1).

While the DIC was collecting information about the commercial ascorbic acid liquids, I did a quick search in my compounding references to see if the ascorbic acid could be extemporaneously compounded without propylene glycol. In Trissel's Stability of Compounded Formulations, 2nd edition, a chapter in the Chemical Stability of Pharmaceuticals, written by Connors et al,12 was cited, which summarized the stability of ascorbic acid in several vehicles for oral use: syrup, USP, glycerin, propylene glycol, sorbitol, 4% carboxymethylcellulose, distilled water and equal part mixtures of glycerin with propylene glycol or sorbitol.13 This summary is shown in Table 2.

Several factors were considered in determining the choice of an ascorbic acid formulation. All of the vehicles that contained propylene glycol were eliminated, along with the vehicles that had short stability dates. This elimination process narrowed the choices to simple syrup, glycerin and sorbitol. Sorbitol was determined as unsuitable because it could cause diarrhea and fluid loss, which arc undesirable side effects, especially in burn patients. Glycerin is a sweet but very thick liquid which may not be palatable for many patients; it would be also difficult to pour down a g-tubc. Glycerin also has side effects to include nausea and vomiting, headache and hyperglycemia. The best option for the vehicle is simple syrup because it is palatable to most patients, is pourablc and has very few side effects.

I notified the clinical pharmacist and the pharmacy manager of the pediatric hospital that T could compound an ascorbic acid 100-mg/mL syrup that is propylene glycol-frec and that it could be kept on hand for inpaticnt use (Table 3).

Summary

Compounding pharmacists can play an important role, especially in the hospital setting, in providing solutions to problem therapies. Without the extemporaneously compounded ascorbic acid syrup, this particular pediatrie patient would have possibly been switched to a parenteral therapy, which is more invasive for the patient, requires more work for the medical staff and is more expensive. Another option would have been to crush tablets, which may not have been palatable for the patient. The therapy could have also been discontinued. The extemporaneous compound provided the needed therapy without increasing the risk of seizures associated with the propylene glycol.

If a medicine service in an institution routinely orders high-dose ascorbic acid therapy with ascorbic acid oral liquid, there are several options that can be considered to prevent propylene glycol toxicity. Many services use preprinted order forms for certain therapies, and the compounded propylene glycol-free ascorbic acid can be listed as an ordering option rather than the commercial product. A policy can be written to address the issue of commercial products with high propylene glycol content and alternative options. Hospitals can flag their computer systems to recognize an order for a high dose of ascorbic acid oral liquid and alert pharmacists to investigate the situation and call the physician. In-services and newsletter articles can be presented to the medical, nursing and the pharmacy staffs about high-dose ascorbic acid therapy using the oral compounded liquid rather than the commercial product. Educating the hospital staff is just as important in preventing adverse events, such as propylene glycol toxicity, as compounding alternative products.

References

1. [No author listed.] MICROMEDEX Healthcare Series. [MICROMEDEX, Inc. Website.] Available at: http://healthcare.micromedex.com. Accessed October 19, 2003.

2. Tanaka H, Matsuda T, Miyagantani Y et al. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: A randomized, prospective study. Arch Surg 2000; 135(3): 326-331.

3. Mazzotta MY. Nutrition and wound healing. J Am Podiatr Med Assoc 1994; 84(9): 456-462.

4. Lacy CF, Armstrong LL, Goldman MP et al. Drug Information Handbook. 8th ed. Washington, DC: American Pharmaceutical Association; 2000-2001:96-97.

5. [No author listed.] American Medical Association. American Medical Drug Evaluations. Chicago, IL: American Medical Association; 1990; 2.

6. Arulanantham K, Genel M. Central nervous system toxicity associated with ingestion of propylene glycol. J PediatrWR; 93(3): 515-516.

7. Martin G, Fi n berg L. Propylene glycol: A potentially toxic vehicle in liquid dosage form. J Pediatr 1970; 77(5): 877-878.

8. Cate JC, Hedrick R. Propylene glycol intoxication and lactic acidosis. N Engl J Med 1980; 303: 1237.

9. Bekeris L, Baker C, Fenton J et al. Propylene glycol as a cause of an elevated serum osmolality. Am J Clin Pathol 1979; 72(4): 633-636.

10. Chicella M, Jansen P, Parthiban A et al. Propylene glycol accumulation associated with continuous infusion of lorazepam in pediatrie intensive care patients. Crit Care Med2002; 30(12): 2752-2756.

11. [No author listed.] World Health Organization. Toxicological evaluation of certain food additives with a review of general principles and of specifications: 17th report of the Joint FAQ/WHO Expert Committee on Food Additives Technical Report Series No. 539. Geneva Switzerland: World Health Organization; 1974.

12. Connors KA, Amidon GL, Stella VJ. Chemical Stability of Pharmaceuticals. 2nd ed. New York, NY: Wiley; 1986.

13. Trissel LA. Trissel's Stability of Compounded Formulations. 2nd ed. Washington, DC: American Pharmaceutical Association; 2000; 30-31.

Linda F. McElhiney, PharmD, RPh

Clarian Health Partners, Inc.

Compounding Pharmacy

Indianapolis, Indiana

Address correspondence to: Linda F. McElhiney, PharmD, RPh, Clarian Health Partners, Inc., Compounding Pharmacy, University Hospital 1451, 550 N. University Boulevard, Indianapolis, IN 46202-5271. E-mail: lmcelhin@clarian.org

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