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Formulations for oral administration of cromolyn sodium

a technology of cromolyn and formula, which is applied in the direction of biocide, immunological disorders, drug compositions, etc., can solve the problems of ineffectiveness, inability to rapidly render biological or chemically active agents particularly vulnerable to such barriers, and inability to effectively deliver active agents, etc., to achieve enhanced absorption and prolong the activity of cromolyn sodium

Inactive Publication Date: 2004-12-23
NOVO NORDISK NORTH AMERICA OPERATIONS AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0027] Prophylactically effective amount--amount of a formulation or composition which is effective to prevent or reduce the incidence or severity of a condition in a living organism to whom it is administered over some period of time.
[0247] As demonstrated by the data in the Examples and Figures, the use of compositions of the subject invention shows significant advantages for the delivery of biologically active agents.

Problems solved by technology

Conventional means for delivering active agents are often severely limited by biological, chemical, and physical barriers.
Biologically or chemically active agents are particularly vulnerable to such barriers.
These agents are rapidly rendered partially or totally ineffective, pass through partially or totally unabsorbed, or are partially or totally destroyed in the gastrointestinal tract by acid hydrolysis, enzymes, or the like.
Absorption of drugs via the gastrointestinal (GI) tract, however, is hampered by natural barriers including acid-induced hydrolysis in the stomach, enzymatic degradation throughout the GI tract, poor solubility in the intestinal environment, and lack of permeation through the epithelial cells.
The latter is particularly problematic because it can exclude the passage of compounds across the tissue based on size, charge and / or lipophilicity.
These systems, however, are highly inefficient and have been shown to cause transient to long-lasting membrane damage.
Such membrane effects have the added disadvantage of allowing nonselective transport of toxic materials.
Cromolyn has a high safety profile but exhibits poor absorption from the gastrointestinal tract.
Cromolyn, when given orally, is poorly absorbed from the gastrointestinal tract because it is highly lipid-insoluble and mainly ionized.

Method used

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  • Formulations for oral administration of cromolyn sodium
  • Formulations for oral administration of cromolyn sodium
  • Formulations for oral administration of cromolyn sodium

Examples

Experimental program
Comparison scheme
Effect test

example 2

[0182] Male and female Cynomolgus monkeys were fasted for 24 hours. Monkeys were gavaged with a solution of delivery agent and cromolyn. Serum obtained from whole blood was acidified and cromolyn extracted with ethyl acetate. The ethyl acetate was added to phosphate buffer for back extraction of cromolyn. Pharmacokinetic parameters were determined from extracted serum by HPLC. The AUC, C.sub.max and T.sub.max from orally dosing capsules containing the delivery agent and cromolyn (25 mg / kg) were 48.8 .mu.g-min / ml, 0.30 .mu.g / ml and 130 minutes, respectively.

example 3

[0183] In order to obtain an in vivo evaluation of the oral administration of cromolyn to sheep, a preparation of delivery agent and cromolyn was prepared and administered to fasted sheep by oral gavage, 15 minutes prior to challenge with ascaris. A control formulation without cromolyn was also administered to an additional group. The biological effect of the cromolyn was assessed using changes in airway resistance of the sheep after challenge with ascaris.

[0184] In one study, the oral doses of cromolyn and delivery agent were administered 15 minutes before ascaris challenge. The results are depicted in FIG. 5, which is a graph depicting the percent airway resistance after ascaris challenge in the sheep over time. As can be seen from FIG. 5, in this study, the oral cromolyn reduced the change in airway resistance by 200%. In animals not receiving cromolyn, the change in airway resistance was plus 500% after ascaris challenge and in animals receiving cromolyn the change in airway res...

example 4

[0188] Cromolyn sodium was orally administered to healthy human subjects in a study designed to evaluate the safety, tolerability, oral absorption and pharmacokinetics data following various doses of cromolyn orally administered in combination with the delivery agent SNAC as capsules. The oral administration was accomplished using capsules containing the specified dose of cromolyn sodium and sodium N-[8-(2-hydroxybenzoyl)amino-]caprylate (SNAC) synthesized, e.g., as decribed in Examples 1 and 8-11 in International Publication Number WO 00 / 46182 by Gschneidner et al. (2000). This study was a randomized, open label, oral, single escalating dose administration study in healthy, fasted volunteers.

[0189] The volunteers were all males between 18 and 50 years of age, in good health, with a body weight resulting in a Body Mass Index (BMI) between 18.0 and 28.0 kg / m.sup.2 inclusive, calculated as the body mass / (Height).sup.2. All laboratory values (electrocardiogram, hematology, serum chemis...

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Abstract

An oral dosage form comprises cromolyn sodium (sodium or disodium cromoglycate), and an acylated amino acid delivery agent.

Description

[0001] This invention relates to delivery of therapeutic polar organic compounds in a bioavailable and bioactive form. This invention further relates to oral administration of polar organic compounds as active agents as part of a therapeutic regimen. This invention further relates to the oral administration of cromolyn in a bioavailable and bioactive form for the treatment of asthma, allergies and viral infections.[0002] This invention is directed to formulations of a delivery agent and cromolyn for oral administration. This invention further relates to formulations of a delivery agent and cromolyn for oral administration that releases cromolyn which is both bioavailable and bioactive for the treatment of asthma, allergies and viral infections.[0003] This invention relates to providing methods for the granulation and encapsulation of a formulation comprising a delivery agent and cromolyn for oral administration. This invention further relates to providing methods for the granulation...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/10A61K9/20A61K9/48A61K31/352A61K47/16A61K47/18A61K47/20A61P11/02A61P11/06A61P19/02A61P29/00A61P37/02
CPCA61K9/4858A61K31/352A61K47/183A61P11/02A61P11/06A61P19/02A61P29/00A61P37/02A61P37/08
Inventor ABBAS, RICHATARBIT, EHUDGOLDBERG, MICHAELWONG, VIVIENSARUBBI, DONALD J.
Owner NOVO NORDISK NORTH AMERICA OPERATIONS AS
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