1. A product for oral delivery of nicotine containing a core comprising a powder of
a) at least one free nicotine salt wherein said nicotine salt is selected from the group consisting of nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate, nicotine bitartrate dihydrate, nicotine sulphate, nicotine zinc chloride monohydrate and nicotine salicylate, and mixtures thereof.
b) at least one pH adjusting agent
c) at least one filler and a water insoluble pouch, wherein said pouch is permeable for saliva and therein dissolved parts of the powder, wherein said product upon contact with purified water gives a pH of at least 6.
2. The product according to claim 1, wherein said nicotine salt is water soluble.
3. The product according to claims 1.
4. The product according to claim 3, wherein said nicotine salt is nicotine bitartrate dihydrate.
5. The product according to claims 1, wherein said pH adjusting agent is selected from the group consisting of carbonates including monocarbonate, bicarbonate and sesquicarbonate, acetates, glycinates, gluconates, borates, glycerophosphates or citrates of alkaline metals or ammonium, phosphate systems including monohydrogenphosphate, dihydrogenphosphate and trihydrogenphosphate, metal hydroxides such as sodium hydroxide and potassium hydroxide, and mixtures thereof.
6. The product according to claim 1, wherein said pH adjusting agent is sodium bicarbonate or sodium carbonate, and mixtures thereof.
7. The product according to claims 1, wherein said pH adjusting agent is encapsulated or embedded.
8. The product according to claim 1, wherein said pH adjusting agent is encapsulated or embedded with a polymer which physically separates the pH adjusting agent from the nicotine salt.
9. The product according to claims 1, wherein said filler is selected from the group consisting of polysaccharides, polyols, sugars, natural fibres, microcrystalline cellulose, cellulose and cellulose derivatives, and mixtures thereof.
10. The product according to claim 1, wherein said product comprises at least one filler which is a sweetener or a flavoring agent.
11. The product according to claim 1 wherein said sweetener is selected from the group consisting of mono- di- tri- and polysaccharides, polyols such as mannitol and maltitol, natural and synthetic sweeteners such as sucrose, glucose, dextrose, maltose, fructose, saccharin, aspartame, acesulfame, sucralose, saccharin and cyclamates, and mixtures thereof.
12. The product according to claim 1 wherein said flavoring agent is selected from the group consisting of bergamot, eucalyptus, orange, mandarin, citrus, lemon, peppermint, mint, menthol, liquorice, wintergreen, tobacco, coffee, vanilla, lime, apple, peach, and mixtures thereof.
13. The product according to claim 1, wherein said pouch is manufactured from material selected from the group consisting of pharmaceutically acceptable membrane materials.
14. The product according to claim 1, wherein said product comprises nicotine in an amount of from 0.1 to 10 mg per unit dose calculated as nicotine base.
15. The product according to claim 11, wherein said product comprises nicotine in an amount of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0 or 9.0 mg per unit dose calculated as nicotine base.
16. The product according to claim 1, wherein said product comprises from 50 mg to 1000 mg of said powder.
17. The product according to claim 1, wherein said product comprises 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 or 950 mg of said powder.
18. A method of making a product comprising the steps of
a) combining ingredients to form a powder, wherein the powder comprises at least one free nicotine salt, at least one pH adjusting agent and at least one filler; and
b) placing the powder in a water insoluble pouch thereby forming a product for oral delivery of nicotine according to claim 1.
19. The method according to claim 18, wherein said method comprising the additional steps of encapsulating or embedding the pH adjusting agent.
20. The method according to claims 18, wherein said method comprising the additional step of granulating the powder.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
We claim:
1. A compound comprising the structure:
15
wherein
B is selected from the group consisting of OH, leaving groups, residues of amine-containing moieties and a residues of hydroxyl-containing moieties;
Y1 is selected from the group consisting of O, S, and NR5;
M is selected from the group consisting of NR3, O and S;
Ar is a moiety which when included in Formula I forms a multi-substituted aromatic or heteroaromatic hydrocarbon or a multi-substituted heterocyclic group;
(m) is zero or a positive integer;
R1-3 and R5 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroakoxy; and
R4 is a polymeric residue.
2. The compound of claim 1, wherein R4 further includes a capping group A, selected from the group consisting of hydrogen, CO2H, C1-6 alkyl moieties, and
16
3. A compound of claim 2, of the formula:
17
4. A compound of claim 3, of the formula:
18
5. The compound of claim 1, wherein R1 R2 and R3 are independently selected from the group consisting of H, methyl and ethyl.
6. The compound of claim 5, wherein R1 R2 and R3 are each H.
7. The compound of claim 1, wherein Y1 is O.
8. The compound of claim 1, wherein the aromatic moiety is selected from the group consisting of:
19
wherein J is O, S, or N-R6; and E and Z are independently C-R7 or N-RY8; and R6-8 are independently selected from the same group as that which defines R1.
9. The compound of claim 1, wherein Ar is
20
10. The compound of claim 1, wherein B is a residue of an amine-containing moiety.
11. The compound of claim 1, wherein B is a residue of an hydroxyl-containing moiety.
12. The compound of claim 1, wherein B is a leaving group selected from the group consisting of N-hydroxybenzotriazolyl, halogen, N-hydroxyphthal-imidyl, p-nitrophenoxy, imidazolyl, N-hydroxysuccinimidyl, thiazolidinyl thione, and an acid activating group.
13. The compound of claim 1 wherein B is a residue of a member of the group consisting of paclitaxel, paclitaxel derivatives, anthracyclines, daunorubicin, doxorubicin, p-hydroxyaniline mustard, Ara-C, cytosine arabinoside and gemcitabine.
14. The compound of claim 1, wherein B is a residue of an enzyme, protein or peptide.
15. The compound of claim 1 wherein R4 has a number average molecular weight of from about 2,000 to about 100,000 Daltons.
16. The compound of claim 15, wherein R4 has a number average molecular weight of from about 5,000 to about 45,000 Daltons.
17. The compound of claim 16, wherein R4 has a number average molecular weight of from about 20,000 to about 42,000 Daltons.
18. The compound of claim 1, wherein R4 is selected from the group consisting of:
C(Y2)(CH2)nO(CH2CH2O)xA,C(Y2)Y3(CH2)nO(CH2CH2O)xA,C(Y2)NR10(CH2)nO(CH2CH2O)xA,(CR11R12)eO(CH2)nO(CH2CH2O)xA,
and
NR10(CH2)nO(CH2CH2O)xA,
wherein
Y2 and Y3 are independently O, S or NR10;
x is the degree of polymerization;
R10, R11 and R12 are independently selected from among H, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
e and n are independently zero, one or two; and
A is a capping group.
19. The compound of claim 1, wherein R4 is selected from the group consisting of:
C(Y2)(CH2)nO(CH2CH2O)x(CH2)nC(Y2),C(Y2)Y3(CH2)nO(CH2CH2O)x(CH2)nY3C(Y2),C(Y2)NR10(CH2)nO(CH2CH2O)x(CH2)nNR10C(Y2),(CR11R12)eO(CH2)nO(CH2CH2)x(CH2)nO(CR11R12)e,
and
NR10(CH2)nO(CH2CH2O)x(CH2)nNR10
wherein
Y2 and Y3 are independently O, S or NR10;
x is the degree of polymerization;
R10, R11 and R12 are independently selected from among H, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
e and n are independently zero, one or two; and
A is a capping group.
20. The compound of claim 1, wherein R4 comprises a polyalkylene oxide.
21. The compound of claim 20, wherein said polyalkylene oxide comprises polyethylene glycol.
22. A compound of claim 1 selected from the group consisting of:
21
23. A compound of claim 1 selected from the group consisting of:
22
24. The compound of claim 1, wherein (m) is zero.
25. The compound of 1, wherein (m) is one.
26. A method of preparing a polymer conjugate, comprising: reacting a compound of
23
wherein
B is selected from the group consisting of OH, leaving groups, residues of amine-containing moieties and a residues of hydroxyl-containing moieties;
Y1 is selected from the group consisting of O, S, and NR5;
M is selected from the group consisting of NR3, O and S;
Ar is a moiety which when included in Formula I forms a multi-substituted aromatic or heteroaromatic hydrocarbon or a multi-substituted heterocyclic group;
(m) is zero or a positive integer;
R1-3 and R5 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroakoxy; and
R4 is a polymeric residue;
with a biologically active compound containing a reactive amino or hydroxy group under conditions sufficient to provide a polymeric conjugate.
27. The method of claim 26, wherein in R4 further comprises a capping
24
28. A method of treating a mammal with prodrugs, comprising:
administering to a mammal in need of such treatment an effective amount of a composition comprising the compound of claim 1, wherein B is a residue of an amine-containing or hydroxyl containing moiety.