This literature review is a compilation of the composition and, in most cases, the preparation instructions for simulated biological fluids that may be used as dissolution media in the evaluation of dissolution profiles and amount of drug released from pharmaceutical dosage forms. The use of simulated biological fluids can give a better understanding of the release mechanisms and possible in vivo behavior of a product and enhance the predictive capability of the dissolution testing. A summary of the major characteristics of the most used routes of administration that may affect dissolution and absorption of drug substances is presented. The routes and simulated biological fluids covered by this review are: • Parenteral: simulated body fluid and simulated synovial fluid. • Oral: fasted-state simulated gastric fluid, fed-state simulated gastric fluid, fasted-state simulated intestinal fluid, fed-state simulated intestinal fluid, simulated colonic fluid, fasted-state simulated colonic fluid, and fed-state simulated colonic fluid. • Buccal and sublingual: simulated saliva. • Pulmonary: simulated lung fluid. • Vaginal: simulated vaginal fluid and simulated semen. • Ophthalmic: simulated tears. Simulated sweat is also included. Some examples of how these simulated biological fluids are used to evaluate dosage forms are included in each route of administration. INTRODUCTION Until some decades ago, most of the conventional pharmaceutical dosage forms were essentially injections, oral formulations (solutions, suspensions, tablets, and capsules), topical creams, and ointments. With the progress of drug delivery technology, novel dosage forms have been developed to overcome the problems associated with conventional drug delivery. Research has been directed toward the use of alternatives to the parenteral route for drugs that cannot be delivered orally. Potential alternative portals of drug entry to the systemic circulation include buccal, sublingual, nasal, pulmonary, and vaginal routes, among others. These routes of administration are also used for the local delivery of drugs directly to the site of action, with consequent reduction in the dose needed to produce a pharmacological effect, eliminating problems related to first-pass metabolism and possibly minimizing systemic side effects (1). An important application of dissolution testing is the prediction of in vivo performance of pharmaceutical dosage forms. The media typically used for quality control dissolution testing do not represent all aspects of the physiological conditions of the most used routes of administration and do not allow correlation with in vivo data. Prediction of dosage form performance in the site where most of the absorption occurs requires adequate simulation of the in vivo conditions. This paper describes some characteristics of the parenteral, oral, buccal and sublingual, pulmonary, ophthalmic, and vaginal routes that are important to consider when developing simulated media. A compilation of the composition and preparation of several simulated biological fluids, including simulated sweat, with potential use as dissolution media is presented. PARENTERAL ROUTE The most used routes of injection are intramuscular, intravenous, and subcutaneous and are normally associated with short-term effects. Novel implant devices that can adequately control drug release and provide a prolonged duration of effect have been developed (1). To evaluate the in vitro drug release from these dosage forms, the dissolution medium should have ion concentrations almost equal to those of the human plasma. Table 1 describes the ionic composition of simulated body fluid (SBF) and human blood plasma. Simulated body fluid was developed initially to evaluate the surface structural changes of glass-ceramics used to manufacture artificial vertebrae, ileum, tooth roots (2), and bioactive material used to repair hard tissues such as artificial middle-ear bone and maxillofacial implants (3). This simulated body fluid was prepared using the reagents listed in Table 2. These reagents were added to 700 mL of water in the order given in Table 2, one by one, after each reagent was completely dissolved. The pH was adjusted to 7.4 with 1 M *Corresponding author. diss-18-03-03.indd 15 8/31/2011 3:22:15 PM dx.doi.org/10.14227/DT180311P15

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Simulated Biological Fluids with Possible Application in Dissolution Testing

Purpose
The aim of this study was to update the compositions of biorelevant media to represent the composition and physical chemical characteristics of the gastrointestinal fluids as closely as possible while providing physical stability during dissolution runs and short-term storage.

Dissolution Media Simulating Conditions in the Proximal Human Gastrointestinal Tract: An Update

Gut instincts: explorations in intestinal physiology and drug delivery.

Angiotensin II type 1 receptor antagonists (ARBs) have become an important drug class in the treatment of hypertension and heart failure and the protection from diabetic nephropathy. Eight ARBs are clinically available [azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan]. Azilsartan (in some countries), candesartan, and olmesartan are orally administered as prodrugs, whereas the blocking action of some is mediated through active metabolites. On the basis of their chemical structures, ARBs use different binding pockets in the receptor, which are associated with differences in dissociation times and, in most cases, apparently insurmountable antagonism. The physicochemical differences between ARBs also manifest in different tissue penetration, including passage through the blood-brain barrier. Differences in binding mode and tissue penetration are also associated with differences in pharmacokinetic profile, particularly duration of action. Although generally highly specific for angiotensin II type 1 receptors, some ARBs, particularly telmisartan, are partial agonists at peroxisome proliferator-activated receptor-γ. All of these properties are comprehensively reviewed in this article. Although there is general consensus that a continuous receptor blockade over a 24-hour period is desirable, the clinical relevance of other pharmacological differences between individual ARBs remains to be assessed.

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

UNLABELLED Telmisartan is an angiotensin II receptor antagonist that is highly selective for type 1 angiotensin II receptors. It was significantly more effective than placebo in large (n >100), double-blind, randomised, multicentre clinical trials in patients with mild to moderate hypertension. Telmisartan 20 to 160 mg once daily produced mean reductions in supine trough systolic blood pressure and diastolic blood pressure of up to 15.5 and 10.5 mm Hg, respectively. Maximum blood pressure reduction occurred with a dosage of 40 to 80 mg/day. Telmisartan 40 to 120 mg/day was as effective as amlodipine 5 to 10 mg/day or atenolol 50 to 100 mg/day in dose-titration studies. Telmisartan 20 to 160 mg/day was generally similar in efficacy to enalapril 5 to 20 mg/day or lisinopril 10 to 40 mg/day in both titration-to-response and other studies. Hydrochlorothiazide was coadministered in most of the titration-to-response studies if patients remained hypertensive. Telmisartan 80 mg/day was more effective than submaximal dosages of losartan (50 mg/day) or valsartan (80 mg/day) and was as effective as a fixed-dose combination of losartan 50 mg plus hydrochlorothiazide 12.5 mg over the last 6 hours of the dosage interval and the whole 24-hour postdose interval. In patients with severe hypertension, telmisartan 80 to 160 mg/day was as effective as enalapril 20 to 40 mg/day (both agents could be titrated and combined sequentially with hydrochlorothiazide 25 mg and amlodipine 5 mg). The addition of hydrochlorothiazide to telmisartan was more effective than each agent alone at lowering blood pressure in patients with hypertension. Telmisartan was well tolerated in patients with mild to moderate hypertension and was significantly less likely to cause persistent, dry cough than lisinopril. CONCLUSION Telmisartan is an effective antihypertensive agent with a tolerability profile similar to that of placebo. Comparative data have shown telmisartan to be as effective as other major classes of antihypertensive agents at lowering blood pressure. Compared with lisinopril, telmisartan is associated with a significantly lower incidence of dry, persistent cough. Therefore, telmisartan is a useful therapeutic option in the management of patients with hypertension.

Telmisartan: a review of its use in hypertension.

Oral anti-diabetic pharmaceutical compositions and the preparation thereof

Topical dermatological compositions containing an acylamino-carboxylic acid compound of the formula ##STR1## wherein R1 is hydrogen, alkyl of 1 to 3 carbon atoms, trifluoromethyl, phenyl, halo-phenyl, nitro-phenyl or biphenylyl, R2 is hydrogen or alkyl of 1 to 3 carbon atoms, R3 is hydrogen, alkyl of 1 to 6 carbon atoms, methylthio-(alkyl of 1 to 6 carbon atoms) or benzyl, R4 is alkyl of 10 to 22 carbon atoms, n is 0, 1 or 2, R5 is alkyl of 8 to 22 carbon atoms, phenyl or biphenylyl, and R6 is hydrogen or alkyl of 1 to 3 carbon atoms; the compositions are useful for the care of the skin.

Dermatological compositions containing an acylamino-carboxylic acid or an alkyl ester thereof

The objectives of this study were to compare two methods for the preparation of bicarbonate buffer, and to compare media prepared with bicarbonate buffer with commonly used biorelevant and pharmacopoeial media in terms of their suitability for dissolution testing. The various media were compared with regard to ease of preparation, robustness and reproducibility of composition. The dissolution of three formulations of a typical Biopharmaceutical Classification System Class II drug (BIXX) was compared in bicarbonate buffer, standard phosphate buffer, a biorelevant buffer (fasted-state simulating intestinal fluid, FaSSIF) and a modified FaSSIF prepared with bicarbonate buffer. The bicarbonate buffer used for dissolution testing was produced by supplying carbon dioxide to a saline solution (0.9% NaCl, to which 12 or 42 mmol NaOH had been added). The bicarbonate buffer had to be prepared in-situ, which proved to be time-consuming, and the pH stability of the bicarbonate buffer could only be maintained under constant CO2 supply. To minimize the mechanical stress caused by inflow and evaporation of gas, the carbon dioxide was supplied above the medium during the dissolution test. Despite taking these measures, use of bicarbonate buffer led to less reproducible dissolution results than the phosphate buffers commonly used to prepare compendial media and FaSSIF, with coefficient of variance values 1.5- to 5-times higher in bicarbonate buffer. It was concluded that although a bicarbonate buffer system would be physiologically relevant for the fasted state in the small intestine, its suitability for dissolution testing is restricted by lack of practicability and poor reproducibility of results.

Is bicarbonate buffer suitable as a dissolution medium

The invention is directed to novel galenic preparation forms for providing an oral anti-diabetic agent having an improved release of active substance and processes for producing these preparation forms. The novel pharmaceutical compositions are characterized in that the onset of the activity and the duration of activity are adapted to the particular needs of diabetics with regard to proper control of the metabolism and the associated proper release of insulin. A basic or acidic excipient in a solvent is added to the anti-diabetic active substance in a quantity such that the active substance is made soluble, and then a solubilizing agent is added. Polyvinyl pyrrolidone is dissolved as carrier in this solution, but the carrier may simultaneously serve as the solubilizing adjuvant. This solution is further processed with other excipients to form corresponding preparation forms.

Oral anti-diabetic pharmaceutical forms and the preparation thereof

This invention relates to vehicles for the administration of mopidamol More specifically, this invention relates to a method of treating cardiovascular disorders, malignancy, or thrombosis in a host in need of such treatment which comprises administering to said host a cardiovascularly, antimetastic, or antithrombotic effective amount of a composition comprised of (i) mopidamol or an acid addition salt thereof and (ii) at least one pharmacologically acceptable acid or acid substance, the total amount of acid from acid addition salt present and acid or acid substance being in a ratio of at least about 1 acid equivalent to 1 mol of mopidamol

Rolf Brickl

Papers

Oral anti-diabetic pharmaceutical compositions and the preparation thereof

Dermatological compositions containing an acylamino-carboxylic acid or an alkyl ester thereof

Is bicarbonate buffer suitable as a dissolution medium

Oral anti-diabetic pharmaceutical forms and the preparation thereof

Oral mopidamol preparation