- Here’s An Opinion On:
- Top Nose Surgeon For Celebrities In New York
Submitted by: Bruce Rehlaender, Ph.D.
A major disadvantage of postoral delivery is that blood flow from the intestine leads into the portal vein which flows directly to the liver. This leads to the phenomenon of first pass clearance, in which drug is metabolized and/or excreted by the liver before it can reach the general circulation. Other routes of administration circumvent this direct flow to the liver and may have other specific advantages.
Sublingual or Buccal Administration:
Buccal or sublingual delivery is typically used for relatively potent drugs that are readily absorbed but undergo extensive first pass clearance. Specific dosage forms designed for the buccal cavity include sublingual tablets, buccal sprays, and buccal patches. These are not as readily accepted as postoral tablets but are still non-invasive and patient friendly.
Technically a dosage form for buccal administration has a quite high probability of success, and marketability and cost of goods would also be reasonable. Unfortunately the high probability of technical success could be a bit of a double-edged sword in that it could be used as the basis for an argument of obviousness by a patent examiner or someone challenging a patent in the future.
Oral Disintegrating Tablet:
Oral disintegrating tablets (ODTs) have been developed for ease of use since they do not require access to water and are suitable for patients who have trouble swallowing pills and capsules. Although these tablets are not typically intended to improve bioavailability, if a drug is absorbed rapidly enough, an ODT may act essentially as a buccal delivery dosage form.
Although the probability of technical success is lower for this approach than for specifically designed buccal dosage form, there are two substantial advantages. First, since ODTs are considered to be simply a different presentation for postoral delivery, any finding of improved bioavailability would be unexpected and would therefore constitute novel intellectual property. The second advantage is that unlike sublingual tablets, buccal sprays, and buccal patches, an ODT is considered to have a marketing advantage over standard postoral tablets and capsules.
Nasal Spray:
Another alternate delivery site is the nasal cavity. Currently, nasal sprays are used almost exclusively for local, rather than systemic, delivery, so there would be an inherent degree of novelty in a nasal spray formulation that would make an intellectual property platform easier to obtain. However, there are reasons why nasal sprays are not commonly used for systemic delivery, and these serve as impediments to this approach.
The primary obstacle to nasal delivery is patient friendliness and patient acceptance. Nasal sprays are inconvenient, are relatively difficult to use, and can cause local irritation. Furthermore, dosing can lack reproducibility due to the coordination required in activating the device while inhaling and the effects of nasal inflammation and mucus secretions. Another limitation of nasal sprays is that the amount of drug delivered is quite limited. A typical device delivers 50 L per spray, and the amount of drug in that volume is limited by the solubility of the drug and/or the extent to which it can be stably suspended.
Nose to Brain Delivery:
An interesting variation on the theme of nasal delivery is so-called nose to brain delivery. Unlike conventional nasal delivery, in which relatively coarse droplets are targeted to the lower lobes of the nasal cavity, this approach involves the use of specialized devices that generate much finer droplets that can be deposited on the olfactory region, located at the top of the upper lobe. The olfactory region is highly enervated and is directly proximal to the brain so that, at least in principle, drug deposited there can be absorbed directly into the brain, bypassing not only the gastrointestinal tract and liver, but the bloodstream as well. This would potentially allow a much lower level of JDTic to be dosed.
Since nose to brain delivery is not yet well established or proven, a strong intellectual property position could be obtained if it did, in fact, lead to substantially enhanced brain deposition. However, unless a drug readily crosses the blood-brain-barrier as it is, the benefits of this approach may not be adequate to justify the downsides. These include patient inconvenience, higher cost, licensing fees for the device, and the likelihood of poorer drug stability in the liquid form. Furthermore, there are outstanding questions about the long term impact of delivering drugs to the olfactory region on the patient s sense of smell.
Subcutaneous Depot or Implant:
A subcutaneous sustained release dosage form could take many forms, from an injectable suspension of slow-release beads to a pellet-like device that can be placed under the skin with a trocar or oversized needle to a large device installed in a surgical outpatient procedure. Naturally, the larger the device is and therefore the more difficult it is to administer, the less frequently it needs to be administered.
The great advantage of a long-term depot or implant is that there is no need for a patient to regularly take his medicine. For treatment of addiction and similar indications, this could be a tremendous selling point for the drug product as it eliminates not only the possibility of a patient forgetting a dose but also of his intentional skipping doses.
If a drug has an extraordinarily long duration of action, an injectable or implantable slow release dosage form would need to have quite a long duration of release to provide a substantial benefit over an oral dosage, which may need to be taken only once a week. The feasibility of such a long-term dosage depends heavily on the required dose of the drug being low enough that an adequate amount could be contained in a reasonably sized device.
Because of the technical complexities of these dosage forms and the wealth of patents around them, development would undoubtedly be carried out under a licensing agreement. Equally doubtless is that the resulting drug product would enjoy strong intellectual property protection.
The downside of an injectable or implantable depot is the inconvenience and invasiveness of administration as well as the increased cost of goods and the loss of revenue to royalty payments for the technology. This means that an adequately compelling case would need to be made for this approach over infrequent oral administration.
Transdermal Patch:
A transdermal patch is another dosage form that lends itself to infrequent administration but is relatively patient friendly. Patches are usually designed to release drug over the course of a day or two.
Because the epidermis is such a formidable barrier, few drugs are good candidates are transdermal delivery. Molecules that can permeate through the stratum corneum, the outermost and most impenetrable layer of the skin, are generally lipophilic and of low molecular weight.
Numerous challenges are involved in developing a transdermal patch dosage form, and these challenges provide ample opportunity for securing intellectual property. A patent could likely be written broadly enough to cover essentially all reasonable approaches to transdermal delivery.
Compliance Indicating Dosage:
Another potential dosage form for use in the treatment of addictive disorders is a dosage form that can indicate non-compliance. For example, if patient was to wear a patch and chose to remove it, such a dosage form would indicate the non compliance to a family member or practitioner.
Although this idea might have some utility, it would be applicable only to limited indications and limited dosage forms. Furthermore, it is not clear how such a dosage form could be designed, and it is likely that development would be very costly. As such, this concept is normally assigned a low probability of success.
Find more articles like this one by searching for “PharmaDirections Formulation Development Blog”.
About the Author: Bruce Rehlaender, Ph.D., Principal, Formulation Development,
PharmaDirections
, a pharmaceutical consulting and project management company specializing in
preclinical development
,
formulation development
and
regulatory affairs
. We direct development for virtual biotechs.
Source:
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