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The act of sublingual absorbtion

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molly bloom Views: 18,824
Published: 15 years ago
Status:       RRR [Message recommended by a moderator!]

The act of sublingual absorbtion

This is very long, and was found on a site for for patents, but there are some very interesting gems in the following. Sorry it is so long, but it completely supports the theory of oil and the mucous membranes.

This invention relates to a dosage form and a method for delivering macromolecular drugs to a human or animal. More particularly, this invention relates to a dosage form and a method for delivering charged or uncharged macromolecular drugs to a warm-blooded animal by transmucosal administration and particularly to the buccal and sublingual tissues of the oral cavity.

The delivery of macromolecular drugs presents one of the greatest challenges in pharmaceutical science. Recently there has been much interest in the use of membranes of the oral cavity as sites of drug administration. Both the buccal and sublingual membranes offer advantages over other routes of administration. For example, drugs administered through the buccal and sublingual routes have a rapid onset of action, reach high levels in the blood, avoid the first-pass effect of hepatic metabolism, and avoid exposure of the drug to fluids of the gastrointestinal tract. Additional advantages include easy access to the membrane sites so that the drug can be applied, localized, and removed easily. Further, there is good potential for prolonged delivery through the buccal membrane. M. Rathbone & J. Hadgraft, 74 Int'l J. of Pharmaceutics 9 (1991). Administration through the buccal mucosa may be better accepted than rectal dosing, for example, and generally avoids local toxic effects, such as has been a problem in nasal administration. B. Aungst & N. Rogers, 53 Int'l J. Pharmaceutics 227, 228 (1989).

The sublingual route has received far more attention than has the buccal route. The sublingual mucosa includes the membrane of the ventral surface of the tongue and the floor of the mouth whereas the buccal mucosa constitutes the lining of the cheek. The sublingual mucosa is relatively permeable, thus giving rapid absorption and acceptable bioavailabilities of many drugs. Further, the sublingual mucosa is convenient, accessible, and generally well accepted. This route has been investigated clinically for the delivery of a substantial number of drugs. It is the preferred route for administration of nitroglycerin and is also used for buprenorphine and nifedipine. D. Harris & J. Robinson, 81 J. Pharmaceutical Sci. 1 (1992).

The buccal mucosa is less permeable than the sublingual mucosa. The rapid absorption and high bioavailabilities seen with sublingual administration of drugs is not generally provided to the same extent by the buccal mucosa. D. Harris & J. Robinson, 81 J. Pharmaceutical Sci. (1992) at 2. The permeability of the oral mucosae is probably related to the physical characteristics of the tissues. The sublingual mucosa is thinner than the buccal mucosa, thus permeability is greater for the sublingual tissue. The palatal mucosa is intermediate in thickness, but is keratinized whereas the other two tissues are not, thus lessening its permeability.

The ability of molecules to permeate through the oral mucosa appears to be related to molecular size, lipid solubility, and ionization. Small molecules, less than about 100 daltons, appear to cross the mucosa rapidly. As molecular size increases, however, permeability decreases rapidly. Lipid-soluble compounds are more permeable through the mucosa than are non-lipid-soluble molecules. In this regard, the relative permeabilities of molecules seems to be related to their partition coefficients. The degree of ionization of molecules, which is dependent on the pKa of the molecule and the pH at the membrane surface, also greatly affects permeability of the molecules. Maximum absorption occurs when molecules are unionized or neutral in electrical charge; absorption decreases as the degree of ionization increases. Therefore, charged macromolecular drugs present the biggest challenge to absorption through the oral mucosae.

Substances that facilitate the transport of solutes across biological membranes, penetration enhancers, are well known in the art for administering drugs. V. Lee et al., 8 Critical Reviews in Therapeutic Drug Carrier Systems 91 (1991) [hereinafter "Critical Reviews"]. Penetration enhancers may be categorized as chelators (e.g., EDTA, citric acid , salicylates), surfactants (e.g., sodium dodecyl sulfate (SDS)), non-surfactants (e.g., unsaturated cyclic ureas), bile salts (e.g., sodium deoxycholate, sodium tauro-cholate), and fatty acids (e.g., oleic acid, acylcarnitines, mono- and diglycerides). The efficacy of enhancers in transporting both peptide and nonpeptide drugs across membranes seems to be positively correlated with the enhancer's hydrophobicity. Critical Reviews at 112. For example, the efficacy of bile salts in enhancing the absorption of insulin through nasal membranes was positively correlated with the hydrophobicity of the bile salts' steroid structure. Critical Reviews at 115. Thus, the order of effectiveness was deoxycholate
Various mechanisms of action of penetration enhancers have been proposed. These mechanisms of action, at least for peptide and protein drugs, include (1) reducing the viscosity and/or elasticity of mucus layer, (2) facilitating transcellular transport by increasing the fluidity of the lipid bilayer of membranes, (3) facilitating paracellular transport by altering tight junctions across the epithelial cell layer, (4) overcoming enzymatic barriers, and (5) increasing the thermodynamic activity of the drugs. Critical Reviews at 117-125.

Many penetration enhancers have been tested and found effective in facilitating mucosal drug administration. Moreover, hardly any penetration enhanced products have reached the market place. Reasons for this include lack of a satisfactory safety profile respecting irritation, lowering of the barrier function, and impairment of the mucociliary clearance protective mechanism. Critical Reviews at 169-70. Another factor that must be dealt with for any enhancer that is to be administered through the buccal or sublingual membranes is the unpleasant taste associated with essentially all of the known enhancers. Further, in order for an enhancer to function adequately, the enhancer and drug combination is preferably held in position against mucosal tissues for a period of time sufficient to allow enhancer assisted penetration of the drug across the mucosal membrane. In transdermal technology, this is often accomplished by means of a patch or other device which adheres to the skin layer by means of an adhesive. In many instances, such as is the case in many macromolecules, the drug may crystallize or not be sufficiently soluble in the enhancer. Thus, a solvent or some other means may be required to provide the degree of drug/enhancer compatibility required to form a functioning system. The isolating of a macromolecular drug/enhancer combination to provide exposure to a designated mucosal area coupled with maintaining the drug in a physical form suitable for passage through the mucosal tissues presents unique problems which need to be overcome for an effective delivery system, particularly through mucus in the oral cavity. This problem is further exacerbated when the drug and/or the enhancer of choice are distasteful in flavor.

Oral adhesives are well known in the art. See, for example, Tsuk et al., U.S. Pat. Nos. 3,972,995; Lowey, 4,259,314; Lowey, 4,680,323; Yukimatsu et al., 4,740,365; Kwiatek et al., 4,573,996; Suzuki et al., 4,292,299; Suzuki et al., 4,715,369; Mizobuchi et al., 4,876,092; Fankhauser et al., 4,855,142; Nagai et al., 4,250,163; Nagai et al., 4,226,848; Browning, 4,948,580; Schiraldi et al., U.S. Pat. No. Re. 33,093; and J. Robinson, 18 Proc. Intern. Symp. Control. Rel. Bioact. Mater. 75 (1991). Typically, these adhesives consist of a matrix of a hydrophilic, e.g., water soluble or swellable, polymer or mixture of polymers which can adhere to a wet mucous surface. These adhesives may be formulated as ointments, thin films, tablets, troches, and other forms. Often, these adhesives have had medicaments mixed therewith to effectuate slow release or local delivery of a drug. Some, however, have been formulated to permit adsorption through the mucosa into the circulatory system of the individual.

There is nothing in the art which is directed specifically with overcoming problems associated with enhancer assisted buccal or sublingual delivery of large drug molecules wherein the drug molecule is subject to crystallization and at least one member of the combination is of objectionable flavor.

As an example, heparin, a drug having potent anticoagulation properties, is a polyanionic molecule having marginal flavor. Native heparin exists mainly in the lungs, intestine, and liver of a variety of mammals. It is also found in high levels intracellularly in mucosal mast cells, connective tissue mast cells and basophilic leukocytes. Commercial heparin preparations are mostly obtained from porcine intestinal mucosa or beef-lung. It is composed of alternating 1-4-linked uronic acid and D-glucosamine residues. The uronic acid residues are either L-iduronic acid or D-glucuronic acid; D-Glucosamine residues are either N-sulfated (major proportion) or N-acetylated (minor proportion). Thus, heparin is a polyanion exhibiting a strong negative charge at neutral pH. Heparin is extremely heterogeneous in both structure and molecular weight because the biosynthesis of the native precursors, heparinproteoglycans (M. W. 750,000 to 1,000,000), are usually not completed. Low molecular weight heparin (LMWH) refers to the fractionated or depolymerized heparin, which has a lower molecular weight than the normal commercial grade heparin, i.e. between about 4000-6000 daltons.

The anticoagulant properties of heparin have been demonstrated to be associated with binding to antithrombin III (AT III). At III is a plasma glycoprotein with molecular weight of approximately 58,000. AT III binds with thrombin very tightly in a 1:1 stoichiometric ratio, which blocks the active site on thrombin and prevents it from interacting with fibrinogen. However, the inhibition rate of thrombin with AT III is low in the absence of heparin. Heparin dramatically accelerates the rate of thrombin inactivation up to 2000-fold. Clinically used heparin can be separated into two distinct fractions according to its affinity for AT III. Approximately 33% of heparin has a high affinity for AT III, which has potent anticoagulant activity (up to 90% of the activity of the unfractionated heparin). A low-affinity heparin binds to the same site on AT III, but with approximately 1000 times lower affinity.

Although anticoagulation is its major pharmacological activity, heparin has many other functions. Heparin inhibits the proliferation of vascular smooth muscle cells and renal mesengial cells, suppresses the delayed-type hypersensitivity, and inhibits angiogenesis. Other pharmacological functions of heparin include antithrombotic effect, antibacterial, antivirus, and antitumor angiogenesis, particularly in combination with cortisone. Although it has been clinically observed that heparin may induce thrombocytopenia, in vitro studies have shown that normal heparin enhances the release of platelets. Moreover, various heparin-binding growth factors can be purified with heparin affinity chromatography.

Heparin has been extensively used in many clinical applications, including cardiac surgery, peripheral vascular surgery, dialysis, autotransfusion, transplantation, the treatment of pulmonary embolism, disseminated intravascular coagulation, and venous thrombosis. The dosage is dependent on the type of application. Heparin has also been used as a prophylactic agent against deep vein thrombosis. The dose of heparin for this treatment is relatively low, e.g., 10,000 U/24 hr for subcutaneous administration. Heparin is also of value in the treatment of thromboembolic disorders, such as pulmonary embolism and arterial thrombosis. These treatments require relatively high doses of heparin, approximately 30,000 U/24 hr.

The transmucosal administration of heparin, particularly via the oral cavity by buccal or sublingual delivery, has been heretofore unavailable. However, as referenced above, there is a need for a practical means for the delivery of heparin or other macromolecules, particularly those in ionic form, by means of buccal or sublingual administration.


It is an object of the present invention to provide a dosage form and method for administering macromolecular drugs to humans and animals through the buccal and sublingual routes.

It is also an object of the invention to provide a dosage form and method for administering charged and uncharged macromolecular drugs to humans and animals that allows easy accessibility to the site of administration.

It is another object of the invention to provide a dosage form and method for administering charged and uncharged macromolecular drugs to humans and animals that promotes high patient acceptance and compliance.

It is a further object of the invention to provide a dosage form and method for administering charged and uncharged macromolecular drugs to humans and animals that allows for localization of dosage forms over a prolonged period to maximize drug absorption.

It is still another object of the invention to provide a dosage form and method for administering charged and uncharged macromolecular drugs to humans and animals that provides acceptable tissue compatibility of the dosage form.

It is yet another object of the invention to provide a dosage form and method for administering charged and uncharged macromolecular drugs to humans and animals through the buccal and sublingual mucosae that avoids the bad taste associated with penetration enhancers.

These and other objects may be accomplished by means of a macromolecular drug/enhancer/polymer formulation comprising a macromolecular drug having a molecular weight in excess of 500 and preferably in excess of about 1000 admixed with a bile salt or bile salt analog enhancer and intimately admixed with a hydrophilic polymer, i.e. a polymer which is either water swellable or soluble, and which serves as a plasticizer for the macromolecular drug and as a position retainer for the drug/enhancer combination against the mucosal tissues. Such a formulation is formulated as a bilayer system wherein the drug/enhancer/polymer combination forms a layer adapted to contact and adhere to the sublingual or buccal mucosa. Overlaying the drug/enhancer/polymer is an outer or cover layer which is substantially impermeable to bile salt enhancer or drug. Macromolecules, such as heparin, and bile salt enhancers have objectionable flavors and the outer layer is designed to reduce or prevent the flow of these components out of the lower layer into the oral cavity by means of saliva or other fluids in the mouth, e.g. by water or other liquids being ingested. This bilayer system can be either in the form of a tablet or a patch. In a tablet the outer layer is an inert, nonadhesive material which facilitates insertion of the tablet by the patient and prevents incidental adhesion of other oral tissue, such as the tongue, to the tablet. In a patch, the outer layer is a film or membrane and is preferably a permselective membrane having a molecular weight cutoff which prevents the outflow of macromolecular drug or bile salt but allows the inflow of water or other smaller molecules into the lower layer. This membrane layer can be either insoluble or of a selected solubility to dissolve after the delivery of the drug and enhancer. This membrane performs the same function as the outer layer of the tablet except that it allows the influx of water and other desired agents or ingredients into the drug/enhancer/adhesive layer. The invention is particularly directed to macromolecular drugs selected from the group consisting of polysaccharides, peptides and proteins having molecular weights of between about 500 and 10,000 or even higher if functional. Exemplary of these are heparin as a polysaccharide and calcitonin as a polypeptide.

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