ABSTRACT
It is a challenging and important project to prolong the in vivo half life of protein and peptide drugs by physicochemical methods without new molecular entities generation. Protein crystallization provides a new strategy for improving the stability and in vivo delivery of these drugs. We show here that recombinant human interferon-alpha (rhIFN) can form spherical crystals. The physical and chemical features of the crystals were characterized, and drug dissolution was determined in vitro. The pharmacokinetics of crystallized interferon after sc injection in rabbit at 1.5 x 10(7) U x kg(-1) was compared to that of soluble form. The crystals were characterized as mono-dispersed spheres, with yield of > 80%, mean diameter size of about 16 microm and crystallinity of 23.2%. The in vitro dissolution behavior of crystallized rhIFN was featured as low initial burst release (21% within the first 2 h) and prolonged cumulative dissolution time up to 72 h without biological potency lost. After sc administration of soluble and crystallized interferon in rabbits, the peak time (T(max)) and half life (t1/2) were prolonged from (1.80 +/- 0.45) h and (1.35 +/- 0.35) h to (13.20 +/- 2.68) h and (10.68 +/- 1.97) h, respectively. The corresponding peak concentration decreased from (1 411.10 +/- 575.28) U x mL(-1) to (721.37 +/- 206.55) U x mL(-1). PK/PD analysis indicated that (96.87 +/- 20.30) % of relative bioavailability was obtained. The research results of this work will provide important academic value and application prospect for improving clinical therapeutic effect and development of biomacromolecules delivery system for protein and peptide drugs.
Subject(s)
Animals , Humans , Male , Rabbits , Antiviral Agents , Chemistry , Pharmacokinetics , Biological Availability , Crystallization , Delayed-Action Preparations , Drug Delivery Systems , Half-Life , Injections, Subcutaneous , Interferon-alpha , Chemistry , Pharmacokinetics , Recombinant Proteins , Chemistry , Pharmacokinetics , Solubility , Surface PropertiesABSTRACT
Crystallization has been widely applied in pharmaceutical formulations as an effective approach to improve the stability and efficacy of small agents. However protein crystals are suffered from limitation in the drug delivery system due to their complex crystallization behaviors. With development of crystallization technologies and their industrial application, protein crystals are receiving more and more attentions as a novel delivery system for biomacromolecules. Crystals with thermodynamic stable structure can improve the physical and chemical stability of protein drugs and present a sustained release behavior. On the basis of pertinent literatures, this review introduces the recent research situation and development process of protein crystals as drug delivery system. Moreover, the crystallization process of proteins, as well as the preparation and potential application are discussed systematically.
Subject(s)
Crystallization , Drug Delivery Systems , Pharmaceutical Preparations , Proteins , ChemistryABSTRACT
<p><b>OBJECTIVE</b>To observe the effect of esmolol application before and during operation on propofol dose required for anesthesia induction and maintenance.</p><p><b>METHODS</b>Forty patients (ASA physical status I or II) undergoing general anesthesia for thyroidectomy were randomized equally into esmolol and control groups. Patients in esmolol group received a loading dose of esmolol at 0.5 mg/kg in 30 ml normal saline over a period of 5 min followed by an intravenous infusion of esmolol at 50 microg.kg(-1).min(-1) until the end of surgery, while patients in the control group were given normal saline in the same manner, in addition to anesthesia with protofol. Perioperative hemodynamic parameters and BIS were measured, and the duration of anesthesia, operation and recovery time from anesthesia were recorded.</p><p><b>RESULTS</b>There were significant differences between the two groups in propofol dose required for anesthesia induction and recovery time from anesthesia, but not in maintenance propofol dose. Patients in esmolol group had significantly lower HR and BIS during tracheal intubation than those in the control group , and no significant differences were found in HR, BP and BIS during operation between the two groups. The hemodynamic parameters during extubation showed less fluctuation in esmolol group.</p><p><b>CONCLUSION</b>Perioperative esmolol administration during anesthesia reduces propofol dose required for anesthesia induction and recovery time from anesthesia, and decreases HR and BIS variation during tracheal intubation and hemodynamic response during extubation without affecting the maintenance propofol dose.</p>