Oral transmucosal drug dosage using solid solution

Details Oral transmucosal drug dosage using solid solution Oral transmucosal drug dosage using solid solution

1999-10-27

2001-07-24

Azpuru, Carlos (Department: 2165)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S464000

Reexamination Certificate

active

06264981

ABSTRACT:

BACKGROUND
1. Field of the Invention
The present invention relates to the improvement of oral transmucosal drug delivery systems. In particular, the invention relates to solid pharmaceutical dosage forms for oral transmucosal delivery of pharmaceutically active substances, and more particularly, to solid dosage forms producing higher dissolution rates and accordingly, higher absorption rates of the pharmaceutically active substance. Furthermore, the present invention provides improved solubility in saliva and mucosal absorption without compromising stability of the solid dosage form during storage.
2. Description of the Prior Art
Solid pharmaceutical dosage forms are well known in the art. Compared to other dosage forms, such as solutions (oral or injection) and vapor or gas inhalation, the oral solid dosage forms are the most preferred dosage forms and they account for eighty percent of all the pharmaceutical products on the market. Solid dosage forms are easier for patient or caregiver to identify, handle and administer. They are also non-invasive and have high patient compliance.
With respect to drug delivery routes, solid dosage forms can be further divided into several groups, gastrointestinal (GI) tract delivery, suppository (rectal, vaginal and urethral) delivery and oral transmucosal delivery. The majority of solid dosage forms on the market are designed for gastro-intestinal delivery. GI delivery is often referred to simply as “oral delivery.” Solids are also commonly delivered as suppositories such as laxatives, contraceptives and hemorrhoid medication. Relatively few drug formulations are designed as solid dosage forms intended to deliver a drug through the oral mucosa. Two such drug formulations are Oralet (®) and Actiq(®).
Despite the overall popularity of other delivery methods, oral transmucosal (OT) delivery is a particularly advantageous delivery route. One of the advantages of OT delivery is that it is a non-invasive drug delivery method. Furthermore, OT delivery has better patient compliance, less risk of infection and lower cost than invasive procedures such as injection and implantation. It also has much shorter onset time, i.e., the time from administration to therapeutic effect, than does oral delivery. A drug absorbed via the oral mucosa will also avoid first pass metabolism, in which the drug is metabolized in the GI tract and liver. Oral transmucosal delivery is simple and can be administered by the caregiver or the patient with minimal discomfort.
Various solid dosage forms, such as sublingual tablets, troches, lozenges, lozenges-on-a-stick, chewing gums, and buccal patches, have been used to deliver drugs via the oral mucosal tissue. U.S. Pat. No. 5,711,961 to Reiner, et al. discloses a chewing gum for the delivery of pharmaceuticals. The chewing gum delivery dosage form of Reiner is primarily directed for patients who may be more disposed to self-administer a drug in chewing gum form as opposed to other less familiar dosage forms. The gum may also be used to mask the taste of various pharmaceutical ingredients. Reiner also discloses the use of the gum formulation to extend the duration of drug delivery.
Transmucosal delivery of drugs is also accomplished through the use of patches which are attached using an adhesive to mucosal surfaces in the oral cavity. Oral transmucosal delivery using a buccal patch is disclosed in U.S. Pat. No. 5,298,256 to Flockhart, et al. The buccal patch may be designed as a “closed” delivery system, that is, the environmental conditions inside the patch are primarily controlled by the formulation. Employing a closed delivery system can facilitate drug delivery, such as allowing the use of enhancers or other permeability facilitators in the formulation which might otherwise be impractical. In an “open” delivery system, such as lozenges or sublingual tablets, the drug delivery conditions are influenced by the conditions of the surrounding environment, such as rate of saliva secretion, pH of the saliva, or other conditions beyond the control of the formulation. Buccal patch delivery also displays a pharmacokinetic delivery profile that can mimic a short term IV infusion.
Solid dosage forms such as lozenges and tablets are commonly used for oral transmucosal delivery of pharmaceuticals. For example, nitroglycerin sublingual tablets have been on the market for many years. The sublingual tablets are designed to deliver small amounts of the potent nitroglycerin, which is almost immediately dissolved and absorbed. On the other hand, most lozenges or tablets are typically designed to dissolve in the mouth over a period of at least several minutes which allows extended dissolution of the lozenge and absorption of the drug.
A lozenge-on-a-stick dosage form of transmucosal drug delivery is disclosed in U.S. Pat. No. 4,671,953 to Stanley, et al. In addition to being non-invasive and providing a particularly easy method of delivery, the lozenge-on-a-stick dosage form allows a patient or caregiver to move the dose in and out of the mouth to titrate the dose. This practice is called dose-to-effect, in which a patient or caregiver controls the administration of the dose until the expected therapeutic effect is achieved. This is particularly important for certain symptoms, such as pain, nausea, motion sickness, and premedication prior to anesthesia because each patient needs a different amount of medication to treat these symptoms. For these types of treatments, the patient is the only one who knows how much medication is enough. Once the appropriate amount of drug is delivered, the patient or caregiver can remove the lozenge, thus, stopping the drug delivery to prevent overdose.
Solid dosage units are made in a number of ways. In a high volume manufacturing facility, solid dosage units can be made by direct compression, injection molding, freeze-drying or other solid processing techniques. Compression, by far, is the most commonly used manufacturing process in making solid dosage units. A typical formulation of solid dosage form consists of active ingredient(s), bulking agent(s), binder(s), flavor(s), lubricant(s) and other excipients.
To benefit from the advantages of oral transmucosal delivery, solid dosage forms must be formulated to take into account the oral cavity's unique environment. In certain aspects, the unique environment of the oral cavity can complicate the transmucosal delivery of the drug. For example, one of the significant aspects of the oral cavity environment with regard to its use as a drug administration route is that there is relatively little solvent into which a solid dosage form can dissolve. Furthermore, the relative amounts of saliva produced in given circumstances can vary widely. On the average, salivary glands produce between 800 to 1500 ml saliva a day. In a resting, unstimulated state, salivary glands produce about 0.5 ml mucous-type saliva per minute, while stimulated salivary glands produce about 1 to 3 ml per minute. During the time required for solid dose drug delivery, about 10 to 15 minutes, the total amount of saliva produced is 10 to 15 ml, which is a small volume compared to 600 to 1000 ml of potential solvent produced in the GI tract.
Similarly, there is a limited period of time during which the solid dosage form can be dissolved and absorbed. An orally (GI tract) delivered solid dose will remain in the GI tract 8 for several hours. An oral transmucosal dose remains in the oral cavity for a mere 10 to 15 minutes. During this period, the solid unit has to be dissolved, and the drug must be released and absorbed. This is a major challenge for formulating the transmucosal solid dosage form.
The absorption of a drug across the mucosal tissue can be described using the equation of Fick's first law:
ⅆ
A
ⅆ
t
=
DK
p
h
·
(
C
1
-
C
2
)
·
S
where dA is the amount of drug delivered over time dt, K
p
is the partition coefficient of the drug between oral mucosal tissue and the drug solution, D is the diffusion coefficient of the drug inside the oral mucosal tissue, S is t

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