Abstract
The formulation of arylpropionic acid derivatives (profens), which are poorly soluble Biopharmaceutical Classification System (BCS) Type II drugs, has a strong impact on their therapeutic action. This article shows that heat-treated powder mixtures of free acid profens with high surface area Cladophora cellulose induces drug amorphization and results in enhanced solubility and bioavailability. Similar mixtures produced using conventional low surface area cellulose, i.e., microcrystalline cellulose, does not produce the same effect. The concept is thoroughly described and links the solid-state characterization data, such as differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infra-red spectroscopy, with in vitro dissolution in biorelevant media and in vivo pharmacokinetic analysis in rats. The concept is demonstrated for several substances from the profens group, including ibuprofen (main model drug), ketoprofen, flurbiprofen, and naproxen. The presented approach opens new ways to produce solid dosage forms of profen drugs in their free acidic form as alternatives to existing analogues, e.g., drug-salt conjugates or soft gel liquid capsules.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used individual medical products
The US Food and Drug Administration (FDA) and the European Medical Products Agency (EMA) recommend that NSAIDs should be prescribed with the lowest effective dose and for the shortest duration in order to avoid drug abuse [3]
Genetic polymorphism has been observed in cytochrome P450 (CYP) iso-enzymes, i.e., CYP2C8 and CYP2C9, which may result in an increased risk of adverse effects [6,7]
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used individual medical products. The benefits of using lysinate or arginate salt conjugates are offset by large stoichiometric quantities of conjugate building agent, e.g., for 400 mg IBU, another 350–400 mg of arginine or lysine is needed The latter makes the tablets more expensive (2–3 times), more bulky, and more difficult to formulate. The characteristic properties of the amorphous solids are their absence of melting enthalpy and enhanced solubility and dissolution rate compared to the same material in the crystalline form. Microcrystalline cellulose (MCC) is an important pharmaceutical excipient It is used as a binder/diluent in oral tablets and capsules both by wet granulation and direct compression. 5 mg of the model drug was mixed with 45 mg of cellulose in a sealed glass vial with cap using a 3-dimensional-type Turbula mixer (Muttenz, Switzerland) for 15 min at 72 rpm for solid-state characterizations
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