| Method of enhancing absorptions of transmucosal administration formulations -> Monitor Keywords |
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Method of enhancing absorptions of transmucosal administration formulationsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Tablets, Lozenges, Or PillsMethod of enhancing absorptions of transmucosal administration formulations description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060051413, Method of enhancing absorptions of transmucosal administration formulations. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The present invention is directed to a method for enhancing absorption of a medicament that is suitable for transmucosal administration, particularly to a method for enhancing absorption of a medicament suitable for sublingual administration. [0003] 2. Description of the Related Art [0004] Transmucosal drug delivery system has been studied for years because it can avoid the liver first-pass effect. The study on this field focuses on how to enhance absorption of the drug. General approaches reported to enhance absorption include the use of various permeation enhancers such as bile salts, surfactants, organic solvents, chelating agents as well as salicylate and Azone.RTM.. [0005] Factors affecting the permeation of a drug via oral mucosa, such as sublingual mucosa, include solubility of the drug, partition coefficient, degree of ionization of the drug, and molecular size and weight of the drug. For a given drug, the molecular size and weight are fixed and cannot be changed. Changes in solubility and degree of ionization will influence partition coefficient and permeability. Therefore, optimization of combined solubility and ionization are variable factors to achieving maximum rate and extent of absorption through oral mucosa such as sublingual mucosa. SUMMARY OF THE INVENTION [0006] A first aspect of the preferred embodiments provides a method for enhancing absorption of a medicament that is suitable for administering transmucosally, such as sublingually in a subject. The medicament used in the preferred embodiments includes a therapeutically effective amount of an active compound or a pharmaceutically acceptable form thereof, or a combination thereof and a pharmaceutically acceptable carrier. [0007] The inventors have found that maximum flux of ionized and non-ionized forms of an active compound of a medicament across the mucosal membrane can be achieved with the attainment of a pH in a mucosal medium by involving certain amount of buffering agents with the medicament. The method of the preferred embodiments comprises providing an environment for the administration with a pH of about: pH = - log .function. ( Ka S i S u ) ( I ) in which K.sub.a is the ionization constant (dissociation constant) of the active compound in water, S.sub.i is the solubility of the ionized form of the compound, and S.sub.u is the solubility of the non-ionized form of the compound. [0008] A second aspect of the preferred embodiments is to provide a method for enhancing absorption of a medicament comprising propranolol or a pharmaceutically acceptable form thereof that is administered transmucosally to a subject, comprising providing an environment of the administration with a pH range of about 7.2 to about 7.8. [0009] A third aspect of the preferred embodiments is to provide a medicament suitable for a transmucosal administration to a subject, comprising an effective amount of propranolol or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, in which the medicament provides an environment of the administration with a pH range of about 7.2 to about 7.8. [0010] A fourth aspect of the preferred embodiments is to provide a method for treating cardiovascular diseases of a subject comprising transmucosally administering a therapeutically effective amount of propranolol or a pharmaceutically acceptable form thereof to the subject in an environment with a pH range of about 7.2 to about 7.8. [0011] Compared to a conventional formulation of propranolol, the formulation of the preferred embodiments can significantly decrease the heart rate in a subject in a very short time, and can be used to treat cardiovascular related diseases (urgent medical conditions) such as atrial fibrillation with rapid heart rate, panic attacks with rapid heart rate, acute hypertension, headache and angina. BRIEF DESCRIPTION OF THE DRAWINGS [0012] FIG. 1 shows heart rates of two healthy subjects after sublingually administering propranolol powder in various pH values; and [0013] FIG. 2 shows a change of heart rate after administered with equivalent sublingual dose of a buffered propranolol tablet of the preferred embodiments versus a conventional Inderal tablet in 2 healthy subjects. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [0014] As stated above, the preferred embodiments provide a method for enhancing absorption of a medicament that is suitably administrated transmucosally. In one embodiment, the medicament is administered sublingually by adjusting the pH of the environment of administration of the medicament. We found that an active compound of a medicament can be significantly absorbed when an environment of the administration of the medicament is kept around: pH max = - log .function. ( Ka S i S u ) ( I ) in which K.sub.a is the ionization constant (dissociation constant) of the active compound of the medicament in water, S.sub.i is the solubility of the ionized form of the compound, and S.sub.u is the solubility of the non-ionized form of the compound. S.sub.i and S.sub.u can be easily obtained by measuring the drug solubility at two extreme pH levels where the ionized or non-ionized species are dominating. [0015] Theoretically, an ionizable medicament to transport across the mucosa includes both the ionized form and the non-ionized form of the medicament. The overall steady-state flux (J.sub.ss) and the apparent permeability coefficient (P.sub.app) of a medicament across the mucosa are the summations of the individual contribution from both the ionized and the non-ionized forms. Therefore, the J.sub.ss and P.sub.app of such a medicament permeate across the mucosa can be expressed by the following equations: J ss .function. ( u ) = d Q u d t A = P u .times. C u ( 1 ) J ss .function. ( i ) = d Q i d t A = P i .times. C i ( 2 ) J ss = J ss .function. ( u ) + J ss .function. ( i ) ( 3 ) P app = P i .times. X i + P u .times. X u ( 4 ) C 0 = C i + C u ( 5 ) [0016] In the above equations, J.sub.ss(u) and J.sub.ss(i) are the steady-state flux of the ionized form and the non-ionized form of the medicament, respectively; Q.sub.u and Q.sub.i are the accumulated amount of the ionized form and the non-ionized form of the medicament penetrated across the mucosa, respectively; A is the surface area of the mucosa; C.sub.0 is the loading concentration of the medicament; P.sub.i and P.sub.u are the permeability coefficient of the ionized form and the non-ionized form, respectively; X.sub.i and X.sub.u are the fraction of the ionized form and the non-ionized form, respectively; and C.sub.i and C.sub.u are the concentration of the ionized and non-ionized forms, respectively. Unlike J.sub.ss(u) and J.sub.ss(i), P.sub.i and P.sub.u are all independent of pH of the solution (environment). Therefore, we would expect that maximal C.sub.i and C.sub.u will be reached at an optimal pH.sub.max, which will be the solubility of the ionized form (S.sub.i) and the non-ionized form (S.sub.u), respectively, and the maximal steady-state flux can be obtained accordingly. ( J ss ) max = P i .times. S i + P u .times. S u ( 6 ) W .times. hen .times. .times. pH .ltoreq. pH max , J ss = P i .times. S i + P u .times. S i .times. K a [ H + ] ( 7 ) W .times. hen .times. .times. pH > pH max , J ss = P u .times. S u + P i .times. S u .times. [ H + ] K a ( 8 ) [0017] It is expected that the best flux of the medicament across the mucosa would be achieved if we could achieve the pH.sub.max in the environment a certain amount of buffering agents in a specific formulation of the medicament. [0018] As used herein, the term "absorption", unless specified otherwise, means "penetration" of the active compound of the medicament through the mucosa. [0019] The term "transmucosal", unless specified otherwise, means any route of the administration via the mucosal membrane. Examples include, but are not limited to, sublingual, nasal, vaginal and rectal. In the preferred embodiments, the administration is preferably performed sublingually. [0020] The term "environment" or "environment of an administration" means an environment where an active compound of a medicament is absorbed by permeation across the mucosa. For example, when the administration is performed sublingually, the environment is saliva, which contains the drug and is "bathing" the sublingual mucosal membrane. Continue reading about Method of enhancing absorptions of transmucosal administration formulations... 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