БИОФАРМАЦЕВТИЧЕСКИЕ И ФАРМАКОКИНЕТИЧЕСКИЕ АСПЕКТЫ ОПИОИДОВ ПРИ РАЗРАБОТКИ НОВЫХ ЛЕКАРСТВЕННЫХ ФОРМ

BIOPHARMACEUTICAL AND PHARMACOKINETIC ASPECTS OF OPIOIDS FOR NOVEL FORMULATIONS DEVELOPMENT

Ciobanu Cristina

Dr. pharm., Associate prof., Department of Drug Technology, “Nicolae Testemitanu” State University of Medicine and Pharmacy,

Republic of Moldova, Chisinau

БИОФАРМАЦЕВТИЧЕСКИЕ И ФАРМАКОКИНЕТИЧЕСКИЕ АСПЕКТЫ ОПИОИДОВ ПРИ РАЗРАБОТКИ НОВЫХ ЛЕКАРСТВЕННЫХ ФОРМ

ABSTRACT

Opioids are a group of drugs used for the management of severe pain. An opioid refers to any substance from a group of analgesic agents derived from the opium poppy seed (Papaver somniferum L.) and many varieties of semi-synthetic and synthetic opioids useful in clinical medicine such as morphine, codeine, methadone, hydromorphone and others. They produce mental relaxation, pain relief, and euphoric feelings. Chronic use of opioids leads to the development of an incapacitating form of dependence in users. To improve efficacy, quality of life, reduce toxicity and addiction nowadays modified and controlled drug delivery systems are evaluated for oral and transdermal delivery which make them more robust in comparison with the impact of short-acting formulations administrated intravenously. The development of novel formulation with opioids requires a paramount biopharmaceutic and pharmacokinetic research. The study aims to presents an overview evaluation of phisico-chemical and pharmacokinetic properties of opioids derivatives and their importance in the improvement of chronic pain management.

АННОТАЦИЯ

Опиоиды - это группа препаратов, используемых для снятия сильной боли. Опиоид относится к любому веществу из группы анальгетиков, полученных из семян опийного мака (Papaver somniferum L.) и многих разновидностей полусинтетических и синтетических опиоидов, используемых в клинической медицине, таких как морфин, кодеин, метадон, гидроморфон и другие. Они вызывают расслабление, облегчение боли и чувство эйфории. Хроническое употребление опиоидов приводит к развитию у потребителей инвалидизирующей формы зависимости. Для повышения эффективности, качества жизни, снижения токсичности и зависимости, в настоящее время разрабатываются модифицированные и контролируемые системы лекарств для пероральной и трансдермальной высвобождения, что делает их более надежными по сравнению с воздействием препаратов короткого действия, вводимых внутривенно. Разработка новой рецептуры с опиоидами требует первоочередных биофармацевтических и фармакокинетических исследований. Цель исследования - представить обзорную оценку физико-химических и фармакокинетических свойств производных опиоидов и их значения в улучшении лечения хронической боли.

Keywords: biopharmacy, Lipinski’s rule of 5, pharmacokinetics, opioids.

Ключевые слова: биофармация, правило Липинского, фармакокинетика, опиоиды.

Nature and human ingenuity have spawned a class of opioid drugs that cure pain and induce feelings of well-being. Unfortunately, overprescribing and misuse of these drugs pose serious risks to individuals [9]. Since the first historical dating of opium, in the Sumerian clay tablets, 8000 years ago, the ancient Greeks, Romans, Egyptians, Indians, Chinese, people of the Middle Ages, Europeans from the Renaissance to the present, used opium as a medicine for various diseases [4]. 

The term opiate refers to compounds structurally related to products found in opium, a word derived from opos, the Greek word for "juice". Opium is obtained from the unripe seed capsules of the poppy plant, Papaver somniferum L. (figure 1).  

Figure 1. Poppy (latin name Papaver somniferum L.)

The milky juice is dried and powdered to make powdered opium, which contains over 20 isoquinoline alkaloids from the group of morphine, codeine, thebaine and benzylisoquinoline derivatives [6].

As a class of medicinal substances opioids can be categorized into three subgroups:

1) naturally occurring compounds (termed opiates) such as morphine and codeine.

2) chemically modified natural compounds (semisynthetic) such as hydrocodone, buprenorphine and oxycodone.

3) completely artificial compounds (synthetic) such as fentanyl, tramadol and methadone, as presented in table 3 [17].

Table 1.

Classification of opioids by origin

In addition, opioids can be categorised according to the type of opioid receptor at which they produce their effects. Classically, there are considered to be three opioid receptors Mu, Delta and Kappa. Opioids are chemicals that produce morphine-like effects in the body; these effects are blocked by antagonists of morphine such as naloxone. Agonists for opioid receptors include various neuropeptides (beta-endorphin, dynorphins, enkephalins, endomorphin) and other synthetic compounds that may have very different chemical structures than morphine. Opiates are a subset of opioids and are naturally occurring molecules that have very similar chemical structure to morphine and would therefore not include the neuropeptides.

Early studies with opioids implied that there must be multiple types of target receptors in the human body because different opioid compounds produced varied levels of effects including analgesia, respiratory depression, pupillary constriction, bradycardia (slow heart rate), reduced gastrointestinal GI motility, smooth muscle spasm, euphoria, sedation, and physical dependence [14].

Opioid receptors are members of the G protein-coupled receptors that act to inhibit adenylate cyclase and thereby reduce intracellular levels of cyclic adenosine monophosphate. Opioids can also have more direct roles in opening potassium channels (preventing nerve hyperpolarization and synapse firing) and to inhibit voltage-gated calcium channels at the cell membrane. Both have the net effect of reducing the excitability of neurons and the release of transmitter calcium to signal other neurons. Opioid receptors are found extensively in the brain and spinal cord, as well as in vascular, gut, lung airway, cardiac, and some immune system cells.

The structure-activity relationship observations, combining physico-chemical  and  biological  data shall be recorded in any stage of incipient formulation [7]. Some opioids are alkaloids and some are peptides. The common structural features are an aromatic ring and a nitrogen atom that is charged at neutral pH. Alkaloids, such as morphine contain multiple fused rings (figure 2), leading to a T-shaped structure [11].

Figure 2. Chemical structure of opioids derivatives [12]

In drug development the major physicochemical parameters such as solubility, molecular mass, pKa, logP, logD, polar surface area are very important. Membrane permeability have been often connected to molecular descriptors such as partition coefficient, molecular weight, number of hydrogen acceptors and donors in molecule called Lipinski rule of 5. Molecules with good membrane permeability have logP <5, molecular weight <500, number of hydrogen bond acceptors <10, and number of hydrogen bond donors <5 [5].

The structural-molecular characteristic of the substances in subject were evaluated using the main online databases [8,13] and are summarized in table 1, all opioids meet the requirements of the Lipinski’s rule.

Table 2.

Physicochemical proprieties of opioids

The absorption, distribution, metabolism, and excretion are important features of any medication. Absorption of oral opiates varies widely. Morphine is irregular in its oral uptake so it is usually given by IV or intramuscular injection (IM). There is, however, a slow-release oral form for those with chronic pain, though the patient must not chew or otherwise crush these tablets or an overdose will occur. Codeine is well absorbed if taken orally, and is usually used as a cough suppressant. Most opiates are subject to significant first-pass metabolism by the liver and are therefore less potent orally than if delivered by IV or injection [14].

The half-life of most morphine derivatives given by mouth is 3 to 6 hours, though some of the first-pass liver metabolites still have considerable analgesic effects. Morphine is not well metabolized by neonates and is relatively long acting causing respiratory depression, so it should not be used during childbirth, where meperidine is a safer choice. Respiration can be restored with the opioid antagonist naloxone, as necessary.

Due to limitations in bioavailability and the formulation challenges associated with some of these pharmaceuticals, parenteral drug delivery is an administration route of paramount importance. This includes intravenous, subcutaneous and intramuscular injection. Indeed, parenteral administration of opioids is needed in patients with gastrointestinal tract disorders, when the opioid need is high or in cases where toxicities associated with intermittent dosing schedules emerge. Morphine sulfate is the most commonly used parenteral opioid and it can be administered as a bolus or continuous infusion.

Oral administration of opioids is efficient and acceptable for most of patients suffering of chronic pain. Indeed, a large set of oral opioid drug formulations is available. Obviously, the main advantage is the ease of administration. Additionally, various polymer systems have been applied successfully resulting in sustained release providing longer and gradual pain relief. The major disadvantage for oral therapy is the first-pass effect and the organ-dependent metabolism, resulting in the necessity of higher dosage forms compared to other types of administration. Minor and less frequent disadvantages occur in patients with dysphagia or neurological impaired persons that cannot swallow [1].

Alternatively, the transdermal route is useful for highly lipophilic opioid such as fentanyl and buprenorphine, whereby the drug is formulated into a polymer reservoir coated with an adhesive polymer or the drug can directly be formulated with the adhesive polymer.

Fentanyl and buprenorphine are equally effective, but the latter drug is less addictive. Transdermal patches have a medium risk for adverse effects and are even approved in children older than 2 years. No mg/kg dosing is however used as over-and under-dosing can occur due to age-related and developmental changes in pharmacokinetics.

Transdermal formulations are often preferred by patients compared to oral controlled-release options. The advantages of transdermal therapy in elderly people include a non-invasive long term administration mode that is independent from intestinal absorption and circumvents first-pass effects [16]. A slow attainment of the peak-plasma concentration also results in improved therapy compliance. Some disadvantages include skin irritation and the limitation of the drug types that can be used with this formulation. The dose is also limited by 240 mg/h, without any possibility for dose adjustments outside the hospital. The second generation of transdermal administration, the iontophoretic delivery system, has a better control of dosage, gives a rapid absorption rate and allows fast clearance [10]. It is important to note that the associated cost of this technique represented a major drawback for its broad applicability. Even though topical opioid therapy is not fully established, it can give analgesia without common opioid side effects. By applying the drug locally, the total opioid dose can be reduced. The only drawback is related to the repeated replacement of wound dressing, as the regeneration of epithelia can be damaged [12].

In the field of drug delivery, nanotechnology aims to formulate therapeutic agents in biocompatible nanocarriers (roughly 10 to 200 nanometer size range), such as nanoparticles, nanocapsules, micelles and liposomes, nanotubes and dendrimers [7]. The major advantage of these formulations is their extended blood circulation time, in combination with enhanced cellular uptake especially by non-healthy, cancerous, tissue, also known as the enhance permeation and retention effect. Furthermore, functionalization of the nanocarriers with targeting ligands allows direct drug delivery to the site of action, improving the bioavailability of the drug. In this way, these nanosystems help to prevent the possible undesired exposure of the drug to off-target tissues [10].

Although nanotechnology for drug delivery is extensively used for therapeutics in cancer, inflammation applications and neurological dissorders, in the literature only few examples have already been reported for opioid administration [17]. This example of a ‘nanotherapeutic’ exemplifies further innovations based on nano-technologies [2].

During the past four decades, controlled release systems have impacted virtually every branch of medicine including ophthalmology, pulmonary, pain medicine, endocrinology, cardiology, orthopedics, immunology, neurology, and dentistry. Polymeric nano/microspheres, liposomes, transdermal patches, and oral controlled-release dosage forms are currently in clinical practice [12].

Polymeric can entrap therapeutic agents and release them in a regulated manner through bulk or surface erosion of the particles, diffusion of the drug through the polymer matrix, or swelling followed by diffusion. Alternatively, drug release can be triggered by the environment or other external events such as changes in pH, temperature, or the presence of an analyte such as glucose.

Different technologies were utilized for slow, extended, controlled, or sustained release of various therapeutic agents using new oral drug delivery systems such as polymeric matrix or gel-forming tablets and oral osmotic pumps. Many of these technologies have been used for extended-release opioid drugs with lower potential of abuse and addiction [3, 15].

The use of these drugs through the modified and controlled release poses significant importance in pain management. Risks like abuse, addiction, respiratory depression, and death can be alleviated through controlled release of opioids at therapeutic levels for prolonged periods. Biodegradable polymeric nanoparticles have been utilized as controlled drug delivery vehicles due to their unique ability of presenting different molecules of interest at their surfaces.

Conclusion. The results of the study highlighted the importance of biopharmaceutical research in association with advanced clinical management, in order to increase the safety of administration. Different technologies are used now in order to lower opioid potential of abuse and addiction.

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