Tobramycin formulations

Nebulized colistin using the IV formulation may be an option in patients with tobramycin-resistant strains or intolerance to inhaled tobramycin. Due to an increased risk of bronchoconstriction after colistin inhalation, patients should pre-treat with albuterol and administer the first doses under medical observation.1,5... 

Newer examples of aminoglycoside antibiotics include amikacin, neomycin (Neosporin, Cortisporin), and tobramycin (TOBI, TobraDex). Injectable tobramycin is used in the treatment of serious infections at many body sites. It has also been formulated in an inhalable dosage form that has a very specific use to treat cystic fibrosis patients having Pseudomonas aeruginosa lung infections. In the form suitable for inhalation by the patient, it delivers the antibiotic directly to the site of infection. 

Patients suffering from cystic fibrosis often use various aerosolized drugs. To reduce the viscosity of the mucus in the airways, recombinant human deoxyribonuclease is used. This enzyme is the first recombinant protein that has been developed for specific delivery to the lungs via the airways. It has a local action on the mucus in the airways and its absorption is minimal. Another drug that decreases the viscosity of the mucus is acetylcysteine. Aerosolized antibiotics are a further group of therapeutics that is widely used by cystic fibrosis patients. Solutions of antibiotics like tobramycin or colistin are used in nebulizers to prevent exacerbation of the disease. Pentamidine has been used for the prophylaxis of Pneumocystis pneumonia in patients infected with HIV virus, while chronic rejection of lung transplants provided a reason to develop an aerosol formulation of cyclosporine A. 

The effects of various formulation factors on the in vitro release characteristics of spherical polymethylmethacrylate implants were studied. Physical and mathematical models were proposed to describe the in vitro release profiles. The in vitro release data could be described by a biexponential equation of the following type fraction of tobramycin remaining in the implant at time t=Aerai+BQ, where a, and P represent the rate constants for the initial rapid and subsequent slow phases of release. The influence of drug loading, volume of dissolution medium, implant size and type of cement and the incorporation of water-soluble additives on the release profiles and a and P rate constants is described. 

The purpose of this study was to adopt a systematic approach to optimize formulation and to characterize the properties of tobramycin-PMMA implants. Tobramycin was selected as it is active against both Gram-positive and Gram-negative bacteria, including gentamicin-resistant Pseudomonas. The specific aims of the study were... 

The influence of the following formulation factors on the release of tobramycin sulphate from PMMA carrier was studied ... 

TOBRAMYCIN SULPHATE FROM POLYMETHYLMETHACRYLATE IMPLANTS 177 Table 2—Effect of formulation factors on computer-generated fast (a) and slow ) phase rate constants... 

Sum) or hollow spherical particles (such as sodium chloride, mannitol, or tobramycin sulfate) are formed depending on the compound. Protein powders such as lysozyme or lactate dehydrogenase can also be produced by this process and can be stabilized through the use of sugars, buffers, and surfactant additives in the formulations. Depending on the solute and conditions of drying, the particles are crystalline in some cases and amorphous in others. ° ... 

Tobramycin Lung deposition study of dry powder formulation with PK data [43]... 

Inhalation of the intravenous formulation of tobramycin can cause bronchoconstriction, as has been confirmed in 26 children with mild to moderate cystic fibrosis (11). Nevertheless, while bronchoconstriction did occur, many patients did not have bronchoconstriction in response to the standard intravenous formulation. The risk of bronchoconstriction may further be reduced by pretreatment with salbutamol. 

Tobramycin solution for inhalation has approval from the Food and Drug Administration (FDA) for maintenance therapy in patients with cystic fibrosis and who are colonized with Pseudomonas aeruginosa. The commercially available formulation is a 300 mg per 5mL. It is a sterile, preservative-free product that is pH adjusted to 6.0. According to the labeling, this product should be used with a specific nebulizer, the Pari C Plus. 

Formulations will increasingly become more complex as the content of the antibiotic is raised within the liposomes [91], and stability is a general concern Dispersions may exhibit aqueous stability of only a matter of days. This issue has partially been addressed through the use of reconstituted lyophilized preps, and a formulation of anamycin has demonstrated over 3 months stability in the solid state [56]. Beauloac et al. [58] have taken this one step further by aerosolizing a dry powder of lyophilized liposome-tobramycin to administer to mice infected with Pseudomonas aeruginosa. [58]. However, the use of powdered preparations does not address the dosing problem. 

Jernigan, Hatch, and Wilson (1988) studied the pharmacokinetics of tobramycin after intramuscular administration in cats. Bioavailability was estimated at 102.5% with maximal concentrations occurring within about an hour. Hence, tobramycin absorption appears rapid and complete. There are few papers modeling the intramuscular absorption of drugs. Swabb et al. (1983) modeled the intramuscular administration of aztreonam, another antibiotic, in humans and found that a simple first-order absorption was adequate to explain the rapid (time to maximal concentrations was 0.88 h) and complete (101% bioavailability) absorption. Similarly, Krishna et al. (2001) also found that first-order absorption was sufficient to model the pharmacokinetics of quinine after intramuscular administration. In both cases, the drugs were formulated in water. 

Administration devices for medicines used to treat asthma and COPD are prescriptirm products, with an exception for some nebulised (medicine) formulations. Medicines such as amphotericin B or antibiotics (coUstimethate sodium, tobramycin sulphate or gentamicin) for nebulisation in CF therapy are sometimes stUl partly prepared by hospital pharmacists, and so are nebulised solutions for bronchial challenge testing. Although product formulation and the method of preparation of formulations for inhalation are not the main subjects of this chapter, recommendations are given in the subparagraphs about nebulisation. 

Newhouse MT, Hirst PH, Duddu SP, Walter YH, Tarara TE, Clark AR, Weers JG (2003) Inhalation of a dry powder tobramycin PuhnoSphere formulation in healthy volunteers. Chest 124(1) ... 

Felt, O., Buri, P, Gumy, R. Ocular bioavaUability of tobramycin after topical administration of formulations based on polysaccharide. In 2nd International Symposium on Experimental Clinical Ocular Pharmacology and Pharmaceutics (1997)... 

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