Mutasem Rawas-Qalaji

Fast-disintegrating sublingual tablets: Effect of epinephrine load on tablet characteristics

The aim of this study was to evaluate the effect of increasing epinephrine load on the characteristics of fast-disintegrating sublingual tablets for the potential emergency treatment of anaphylaxis. Four tablet formulations, A, B, C, and D, containing 0%, 6%, 12%, and 24% of epinephrine bitartrate, respectively, and microcrystalline cellulose:low-substituted hydroxypropyl cellulose (9∶1), were prepared by direct compression, at a range of compression forces. Tablet weight variation, content uniformity, hardness, disintegration time, wetting time, and friability were measured for each formulation at each compression force. All 4 tablet formulations at each compression force were within the United States Pharmacopeia (USP) limits for weight variation and content uniformity. A linear increase in compression force resulted in an exponential increase in hardness for all formulations, a linear increase in disintegration and wetting times of A, and an exponential increase in disintegration and wetting times of B, C, and D. At a mean±SD hardness of ≥2.3±0.2 kg, all tablet formulations passed the USP friability test. At a mean±SD hardness of ≤3.1±0.2 kg, all tablet formulations resulted in disintegration and wetting times of <10 seconds and <30 seconds, respectively. Tablets with drug loads from 0% to 24% epinephrine can be formulated with hardness, disintegration times, and wetting times suitable for sublingual administration.

Advances in Ocular Drug Delivery

Eye drops have long been the primary ocular drug delivery dosage form used to treat ocular disorders ranging from superficial conditions to intravitreal diseases. The ocular anatomical structure and physiological protective mechanisms are one of the most formidable barriers to drug penetration that have significantly reduced the drug’s efficacy and target selectivity while sometimes causing ocular tissue damage. There are many new and innovative advances in ocular drug delivery due to better understanding of the structure and function of the eye, the nature of its diseases, and how to overcome or utilize its protective barrier(s), which resulted in increased bioavailability and longer duration of action of the administered drugs, therefore, more effective disease management. We seek in this article to present a comprehensive overview of the basic required knowledge about the barriers for drug delivery to the eye and the major breakthroughs and advances in ocular drug delivery to the anterior, posterior and intravitreal segments of the eye.

Long-term stability of epinephrine dispensed in unsealed syringes for the first-aid treatment of anaphylaxis

BACKGROUND When epinephrine autoinjectors are unavailable or unaffordable, patients at risk for anaphylaxis in the community are sometimes provided with an unsealed syringe containing a premeasured epinephrine dose for use in first-aid treatment of anaphylaxis episodes. OBJECTIVES To study the stability of epinephrine solution in unsealed syringes under conditions of high ambient temperature, low vs high humidity, and light vs dark. METHODS Forty unsealed syringes each containing an epinephrine dose of 0.3 mg (as a 1-mg/mL epinephrine solution) were stored at 38 degrees C for 5 months, with 10 syringes at each of 4 different standardized storage conditions: dark and light at low (15%) humidity and dark and light at high (95%) humidity. Duplicate syringes were removed monthly from each storage environment and analyzed for epinephrine content vs control syringes. RESULTS The epinephrine dose, expressed as the percentage remaining of the mean control dose, was below compendial limits (90% to 115% of label claim) by 3 months after storage at 38 degrees C and low humidity and by 4 months after storage at 38 degrees C and high humidity. Light had no significant effect. CONCLUSION In hot climates, if an unsealed syringe prefilled with an epinephrine dose is provided for the first-aid treatment of anaphylaxis, it should be replaced every few months on a regular basis with a new syringe containing a fresh dose of epinephrine.

Epinephrine (adrenaline) absorption from new-generation, taste-masked sublingual tablets: A preclinical study

From the Center for Allergy and Inflammation, Division of Allergy and Infectious Diseases, the Division of Cardiology, and the Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Wash; the Department of Anesthesiology, University of Washington, Seattle, Wash; and the Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. E-mail: dayars@u.washington.edu. Disclosure of potential conflict of interest: D. K. Stewart has provided legal consultation/expert witness testimony on a potential malpractice case. The rest of the authors declare that they have no relevant conflicts of interest.

Fast-Disintegrating Sublingual Epinephrine Tablets: Effect of Tablet Dimensions on Tablet Characteristics

ABSTRACT The purpose of this study was to evaluate the effect of changing dimensions on the hardness (H), disintegration time (DT), and wetting time (WT) of fast-disintegrating epinephrine tablets for sublingual administration as potential first aid treatment for anaphylaxis. Tablet formulations I and II, containing 0% and 10% epinephrine bitartrate, respectively, and weighing 150 mg were prepared by direct compression. Formulations were compressed at a range of forces using an 8/32″ die with concave punches (CP); a 10/32″ and an 11/32″ die with CP and flat punches (FP). Tablet weight variation, content uniformity, thickness, H, DT, and WT were measured. The 8/32″, 10/32″, and 11/32″ dies resulted in tablet thickness of ranges 0.25–0.19″, 0.17–0.1″, and 0.16–0.08″, respectively. The DT and WT using the 8/32″ die were ≤10 and ≤30 sec, respectively, at H ≤5.4 ± 0.2 kg for formulation I, and H ≤5.4 ± 0.3 kg for formulation II. The DT and WT were ≤10 and ≤30 sec, respectively, using 10/32″ die/CP, 10/32″ die/FP, 11/32″ die/CP, and 11/32″ die/FP at H ≤6.2 ± 0.6 kg, ≤6.8 ± 0.4 kg, ≤4.9 ± 0.1 kg, and ≤7.2 ± 0.3 kg, respectively, for formulation I. For formulation II, the DT and WT were ≤10 sec and ≤30 sec, respectively, when H < 4 kg. No difference in DT and WT was observed between concave and flat tablets. The 11/32″ and 10/32″ dies resulted in more ideal tablet dimensions for sublingual administration, but H must be maintained <4 kg to ensure rapid DT and WT.

Rapidly-disintegrating sublingual tablets of epinephrine: role of non-medicinal ingredients in formulation development.

Epinephrine is the drug of choice in the management of anaphylaxis. For first-aid treatment in the community, epinephrine autoinjectors (E-autos) are commonly prescribed, but are underutilized. In our laboratory, we developed a series of first-generation rapidly-disintegrating sublingual tablets (RDSTs) containing 40mg of epinephrine. One RDST had similar bioavailability to epinephrine 0.3mg from an auto-injector, as confirmed in a validated rabbit model, while other formulations containing different non-medicinal ingredients (NMIs) and with similar in vitro characteristics demonstrated much lower bioavailability. Subsequently, we evaluated the effect of changing the grade and proportion of NMIs, specifically mannitol and microcrystalline cellulose (MCC), on the in vitro characteristics of second- and third-generation RDSTs. Weight variation, content uniformity, breaking force, and friability were tested using official USP methods. Novel validated methods that simulate ambient conditions of the sublingual cavity were developed to test disintegration time, wetting time, and dissolution. Using these methods, it was possible to measure the effects of making small changes in NMIs on the in vitro characteristics of the formulations. The RDST formulation that resulted in the best in vitro characteristics contained the optimum proportion of mannitol and a specific ratio of coarse and fine particle grades of MCC. Appropriate comparative testing resulted in the selection of the RDST with the optimum in vitro characteristics.

Epinephrine autoinjectors: Does freezing or refrigeration affect epinephrine dose delivery and enantiomeric purity?

Epinephrine (adrenaline) is the first-line treatment in anaphylaxis. In community settings, failure to carry epinephrine autoinjectors (EAIs) consistently and failure to inject epinephrine promptly when anaphylaxis occurs can increase the risk of fatality. Instructions about EAI storage and stability of epinephrine are included in the prescribing information for all EAIs. As an example, the US EpiPen monograph states:

Adrenaline (epinephrine) microcrystal sublingual tablet formulation: enhanced absorption in a preclinical model.

For anaphylaxis treatment in community settings, adrenaline (epinephrine) administration using an auto‐injector in the thigh is universally recommended. Despite this, many people at risk of anaphylaxis in community settings do not carry their prescribed auto‐injectors consistently and hesitate to use them when anaphylaxis occurs.The objective of this research was to study the effect of a substantial reduction in adrenaline (Epi) particle size to a few micrometres (Epi microcrystals (Epi‐MC)) on enhancing adrenaline dissolution and increasing the rate and extent of sublingual absorption from a previously developed rapidly disintegrating sublingual tablet (RDST) formulation in a validated preclinical model.

Epinephrine doses delivered from auto-injectors stored at excessively high temperatures

Abstract Context: Prompt injection of epinephrine (adrenaline) from epinephrine auto-injectors (EAIs) is the primary treatment for anaphylaxis in out-of-hospital settings. Storage of EAIs at room temperature (25 °C) is advised; however, storage at excessively high temperatures sometimes occurs. To our knowledge, there are no previous publications on the doses of epinephrine ejected from EAIs after storage at such temperatures. Objective: We examined the epinephrine doses delivered from activated EAIs stored constantly or cyclically at 70 °C. Methods: Twenty-five in-date EAIs were stored constantly or cyclically at 70 °C (excessive heat) or 25 °C (controls) for 5 d or 10 d. EAIs were activated and the epinephrine doses in the ejected solutions were measured using HPLC-UV. The enantiomeric purity of epinephrine was also measured by HPLC-UV. Results: Control EAIs ejected a volume of 0.300 ± 0.006 mL containing 103.7 ± 3.3% of labeled dose (LD). After 5 d or 10 d of constant storage at 70 °C and activation at 70 °C, EAIs ejected a volume of 0.367 ± 0.008 mL containing 96.8 ± 3.8% LD and 0.373 ± 0.007 mL containing 77.7 ± 3.3% LD, respectively. After 5 d of cyclic storage at 70 °C and cooling to 25 °C before activation, EAIs ejected a volume of 0.311 ± 0.008 mL containing 87.2 ± 1.9% LD. Under the experimental conditions of this study, the resultant chromatographic peaks of epinephrine solutions from all EAIs represented only the pure l-enantiomer of epinephrine. Conclusion: EAIs should be stored under recommended conditions of the manufacturer. EAIs stored at excessively high temperatures cannot be used to treat humans while still hot, and when cooled, cannot be relied on to deliver the labeled epinephrine dose in anaphylaxis.

Effect of lipid viscosity and high-pressure homogenization on the physical stability of “Vitamin E” enriched emulsion

Abstract Recently there has been a growing interest in vitamin E for its potential use in cancer therapy. The objective of this work was therefore to formulate a physically stable parenteral lipid emulsion to deliver higher doses of vitamin E than commonly used in commercial products. Specifically, the objectives were to study the effects of homogenization pressure, number of homogenizing cycles, viscosity of the oil phase, and oil content on the physical stability of emulsions fortified with high doses of vitamin E (up to 20% by weight). This was done by the use of a 27-run, 4-factor, 3-level Box–Behnken statistical design. Viscosity, homogenization pressure, and number of cycles were found to have a significant effect on particle size, which ranged from 213 to 633 nm, and on the percentage of vitamin E remaining emulsified after storage, which ranged from 17 to 100%. Increasing oil content from 10 to 20% had insignificant effect on the responses. Based on the results it was concluded that stable vitamin E rich emulsions could be prepared by repeated homogenization at higher pressures and by lowering the viscosity of the oil phase, which could be adjusted by blending the viscous vitamin E with medium-chain triglycerides (MCT).