Abstract
Addiction to heroin is a common problem in many countries around the world. Nowadays, addiction has been accepted as a chronic, relapsing psychiatric disorder. Pharmacological treatments have been developed, but stabilisation of drug use and harm reduction have become the focus of therapy for a subgroup of chronic addicts, for
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whom treatment options are limited. Presently, there is considerable interest in heroin-assisted treatment (HAT): (co-)prescription of heroin to chronic, treatment-refractory opioid dependent patients. Several countries have clinical trials on this subject that need pharmaceutical heroin (diacetylmorphine) to prescribe to the patients.
This thesis describes the development of pharmaceutical preparations of diacetylmorphine intended for prescription to addicts. The research was based on the existing knowledge of the properties of pure diacetylmorphine and street heroin as well as of routes of administration investigated clinically and those utilised on the street. Furthermore, pharmaceutical heroin has to comply with the usual requirements of efficacy, safety, and quality of pharmaceutical products. Acceptability to patients is also an important requirement, especially since HAT is aimed at treatment-resistant addicts, who often have to be encouraged to participate in a treatment program. Therefore, the most suitable dosage form would have a pharmacokinetic profile mimicking that of diacetylmorphine for injection, with rapid peak concentrations of diacetylmorphine and 6-acetylmorphine, ensuring the 'flash' effect and the sustained presence of morphine(-6-glucuronide) creating the prolonged euphoria.
Injection of heroin is the most widely used mode of administration among addicts. We therefore describe the development of a freeze-dried dosage form of diacetylmorphine hydrochloride, containing 3 gram/vial, intended for multiple use by injection.
Heroin smoking ('chasing the dragon') is the second most popular route of administration by addicts. In this procedure, heroin powder is heated on a piece of aluminium foil (using a cigarette lighter) and the vapours that arise after volatilising are subsequently inhaled through a tube or straw in the mouth. This mode of administration has a 52% bioavailability compared to injected heroin and it has pharmacokinetic and pharmacodynamic profile that would make it acceptable to addicts in HAT. Therefore, this thesis extensively describes the development of diacetylmorphine for inhalation after volatilisation. Thermal analysis experiments showed that addition of caffeine anhydrate to diacetylmorphine base resulted in a lower melting temperature and a higher volatilisation rate for the mixture than for diacetylmorphine base alone. More elaborate in vitro volatilisation experiments showed that volatilisation of diacetylmorphine/caffeine mixtures resulted in sufficient amounts of diacetylmorphine in vapour and in particles small enough for efficient deposition in the lungs. The powder mixture containing 75% w/w diacetylmorphine base and 25% w/w caffeine anhydrate was preferred for development of pharmaceutical heroin for inhalation after volatilisation.
This mixture was dosed and packaged into sachets using a micro dose auger filler machine. The filling process was characterised, optimised, and validated and we describe the development of the manufacturing process and the in-process controls included therein, as well as the quality control of the final product.
Finally, this thesis contains three studies concerning the administration of diacetylmorphine for inhalation after volatilisation: a pharmacokinetic study comparing two methods for volatilisation of diacetylmorphine/caffeine tablets, an investigation into the use of deuterodiacetylmorphine as a marker for use of illicit heroin by patients in HAT, and the detection of possible degradation products present in the fumes that patients inhale.
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