Eye on Excipients: Formulating for Lactose Intolerance

Cetirizine dihydrochloride is a second-generation antihistamine that is used to treat hay fever, allergies, angioedema, and urticaria (hives). As an H1 antagonist, cetirizine relieves the symptoms of allergic reactions by temporarily blocking the action of histamine at the H1 receptors^1,2. Cetirizine is one of the most common H1 antihistamines, but many cetirizine tablets on the market contain lactose, making them unsuitable for lactose-intolerant patients³. Approximately 33 percent of the global population is affected by lactose intolerance—the inability to digest the milk sugar lactose. This condition is caused by a shortage of the enzyme lactase, which can lead to several gastrointestinal symptoms, including abdominal pain, bloating, diarrhea, gas, and nausea. Almost all infants produce sufficient amounts of lactase, but about 75 percent of adults have impaired lactase activity, especially in large parts of Asia and Africa. For this reason, it’s important to study alternative excipients for the development of lactose-free drug products^4,5. 

A potential substitute for spraydried lactose in cetirizine tablets is dextrates, a directly compressible, water-soluble tablet filler and binder with comparable powder characteristics and functional tablet parameters to spray-dried lactose. This article presents the results of a study designed to determine whether dextrates is a suitable substitute for lactose in marketed cetirizine tablets. The product used for the study was Emdex⁶, which is monographed as dextrates in the USP. It is composed of 95 percent glucose monohydrate and 5 percent oligosaccharides resulting from the enzymatic hydrolysis of starch.

Reference product 

Reactine was selected as the study’s reference product⁷. The white oblong film-coated tablets with breaklines measured 4 by 10 millimeters, weighed 120 milligrams, and sustained an average crushing strength of 79 newtons (Photo 1). In addition to 10 milligrams of cetirizine dihydrochloride, the Reactine tablets contained microcrystalline cellulose (MCC) and lactose monohydrate as filler-binders, silicon dioxide as a glidant, and magnesium stearate as a lubricant. The tablets were coated with Opadry Y-1-7000, which is composed of hypromellose, titanium dioxide, and polyethylene glycol (PEG) 400⁸. 

Study design 

The cetirizine tablets were reformulated in both a lactose-based version to match the original reference product formulation as closely as possible, and in a lactose-free version that replaced the spray-dried lactose with dextrates. Both formulations were compressed into the same format and size as the original tablets using compaction forces between 2 and 15 kilonewtons. The tablets were then compared in terms of powder flow, ejection force, and functional tablet characteristics such as crushing strength and friability. Coated tablets with the same crushing strength as the reference product were produced, and their disintegration time and dissolution profiles were analyzed and compared with the original cetirizine tablets. 

Powder characteristics of dextrates and spray-dried lactose 

The similarities between the powder characteristics of dextrates and spray-dried lactose are shown in Table 1. Both are water-soluble, crystallized powders with a porous structure and a spherical particle shape (Photo 2). The particle shape and high bulk density results in excellent powder flow for both materials. Furthermore, both excipients are appropriate for direct compression applications and mainly deform by brittle fracture. 

Cetirizine tablet reformulation 

The quantitative composition of the reformulated tablets is shown in Table 2. The proportion between MCC and lactose monohydrate in the original tablets was assessed by separating water-soluble and insoluble components and weighing them out. In addition to the API, the water-soluble fraction mostly contained lactose monohydrate, whereas the water-insoluble fraction chiefly consisted of MCC, resulting in relative proportions of about 30 percent MCC and 59.7 percent lactose monohydrate. Furthermore, 1 percent silicon dioxide and 1 percent magnesium stearate were added to the formulation. The only difference between the lactose-based tablets and the dextrates-based tablets was the substitution of dextrates for lactose monohydrate. 

Results and Discussion 

Powder flow and tablet characteristics of uncoated tablet cores

The lactose- and dextrates-based formulations showed similar results in terms of powder flow, ejection force, and compactibility (Figure 1). Both formulations had excellent flowability resulting in a very low Flodex index of 8 millimeters. The ejection force of both types of tablets remained below 200 newtons, even at a high compaction force of 15 kilonewtons, and an appropriate tablet hardness was obtained. Both formulations produced tablets with a very low friability. At moderate compaction forces (≥ 7 kilonewtons) the friability decreased below 0.1 percent (Table 3). 

Coated tablets

To obtain a final tablet hardness of about 80 newtons, as measured for the reference product, tablet cores with a crushing strength of 50 newtons were pressed and then coated with a weight gain of 4 percent. For both formulations, only low compaction forces of 5.75 and 4.15 kilonewtons were required to form tablet cores with an adequate tablet hardness (Table 4). After the coating process, a crushing strength of 76 and 80 newtons was determined in the lactose- and dextrates- based formulations, respectively. The coated tablets disintegrated within 3 minutes and exhibited a comparable tablet weight and height as the original cetirizine tablets. The dissolution profiles of the lactose- and dextrates-based tablets as well as the reference product showed a high degree of similarity (Figure 2). Slight differences between the formulations could be observed during the first few minutes, but after 10 minutes the total cetirizine amount was released in all formulations. 

Conclusion 

Like spray-dried lactose, dextrates is a water-soluble filler-binder with brittle fracture as the main binding mechanism. Dextrates and spray-dried lactose show great similarity in terms of particle morphology, bulk density, and flowability. Therefore, dextrates is an ideal substitute for spraydried lactose when reformulating cetirizine tablets to make them suitable for lactose- intolerant patients. The dextrates- based formulation was fully equivalent to the lactose-based tablets and the marketed product Reactine with respect to powder characteristics and tablet parameters, such as compactibility, disintegration time and dissolution profile.

References

1. Bopp, A. & Herbst, V. (2010). Handbuch Medikamente: vom Arzt verordnet: für Sie bewertet, 8. Auflage, Berlin: Stiftung Warentest.

2. Armstrong, A.W. & Kvedar, J.C. (2008). Histamine Pharmacology. In: Principles of Pharmacology - The Pathophysiologic Basis of Drug Therapy (eds. Golan, D.E. et al.), 2nd Edition, Baltimore (MD): Lippincott Williams & Wilkins.

3. Schwabe, U. & Paffrath, D., Hrsg. (2007). Arzneiverordnungsl Report 2007. Aktuelle Daten, K o s t e n , Tr e n d s und Kommentare. Heidelberg: Springer Medizin Verlag.

4. Mattar, R. et al. (2012). Lactose intolerance: diagnosis, genetic, and clinical factors. Clinical and Experimental Gastroenterology, 2012:5 113- 121.

5. Deng, Y. et al. (2015). Lactose Intolerance in Adults: Biological Mechanism and Dietary Management. Nutrients, 2015, 7, 8820-8835.

6. Emdex is a registered trademark of JRS Pharma, Rosenberg, Germany.

7. Reactine is a registered trademark of McNeil Consumer Healthcare, Fort Washington, PA.

8. Opadry Y-1-7000 is a registered trademark of Colorcon, Harleysville, PA.