GB2232889A - Pharmaceutical composition comprising 3-(n-piperidinomethylazino)methylrifamy- cin s as active ingredient - Google Patents
Pharmaceutical composition comprising 3-(n-piperidinomethylazino)methylrifamy- cin s as active ingredient Download PDFInfo
- Publication number
- GB2232889A GB2232889A GB8905489A GB8905489A GB2232889A GB 2232889 A GB2232889 A GB 2232889A GB 8905489 A GB8905489 A GB 8905489A GB 8905489 A GB8905489 A GB 8905489A GB 2232889 A GB2232889 A GB 2232889A
- Authority
- GB
- United Kingdom
- Prior art keywords
- starch
- fce
- methylrifamycin
- pharmaceutical composition
- piperidinomethylazino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- RYJAEZQKMOPBHP-YNTMCLQCSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,27,29-tetraoxo-26-[(E)-[(E)-piperidin-1-ylmethylidenehydrazinylidene]methyl]-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25-heptaen-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2C(=O)C(\C=N\N=C\N4CCCCC4)=C(NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C(=O)c2c(O)c3C RYJAEZQKMOPBHP-YNTMCLQCSA-N 0.000 title claims description 8
- 239000004480 active ingredient Substances 0.000 title description 6
- 239000000203 mixture Substances 0.000 claims description 7
- 239000013543 active substance Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 235000013681 dietary sucrose Nutrition 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 229960004793 sucrose Drugs 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 3
- 229940032147 starch Drugs 0.000 claims description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 235000003599 food sweetener Nutrition 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 229940067606 lecithin Drugs 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 229920001592 potato starch Polymers 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000003765 sweetening agent Substances 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 235000012222 talc Nutrition 0.000 claims description 2
- 239000000080 wetting agent Substances 0.000 claims description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims 1
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 235000010489 acacia gum Nutrition 0.000 claims 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 claims 1
- 229940072056 alginate Drugs 0.000 claims 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims 1
- 239000000975 dye Substances 0.000 claims 1
- 229950008882 polysorbate Drugs 0.000 claims 1
- SRGITGUCGGVOQM-YNQXYWRISA-N fce 22250 Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C/C=C(C)/C(=O)NC2=C(O)C=3C(O)=C4C)C)OC)C4=C1C=3C(=O)\C2=C\N\N=C\N1CCCCC1 SRGITGUCGGVOQM-YNQXYWRISA-N 0.000 description 13
- WRAPOXJPMSGPAZ-BJXRANMGSA-N fce 22807 Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)N=C2C(=O)C=3C(O)=C4C)C)OC)C4=C1C=3C(=O)\C2=C\N\N=C\N1CCCCC1 WRAPOXJPMSGPAZ-BJXRANMGSA-N 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 9
- 229960001225 rifampicin Drugs 0.000 description 5
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- -1 rifampicin Chemical class 0.000 description 4
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical class OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004053 quinones Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930189077 Rifamycin Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- ATEBXHFBFRCZMA-VXTBVIBXSA-N rifabutin Chemical class O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC(=C2N3)C(=O)C=4C(O)=C5C)C)OC)C5=C1C=4C2=NC13CCN(CC(C)C)CC1 ATEBXHFBFRCZMA-VXTBVIBXSA-N 0.000 description 1
- BTVYFIMKUHNOBZ-QXMMDKDBSA-N rifamycin s Chemical class O=C1C(C(O)=C2C)=C3C(=O)C=C1NC(=O)\C(C)=C/C=C\C(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C(C)C(OC)\C=C/OC1(C)OC2=C3C1=O BTVYFIMKUHNOBZ-QXMMDKDBSA-N 0.000 description 1
- 229940081192 rifamycins Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
PHARMACEUTICAL COMPOSITION COMPRISING 3-(N-
PIPERDINOMETHYLAZIN0)METHURIFAMYCIN S AS ACTIVE INGREDIENT The present invention relates to pharmaceutical compositions comprising 3(N-piperidinomethyl-azino)methylrifamycin 5 as active ingredient.
US-A-4,447,432 and the corresponding patent applications GB-A-2,110,677 and JP-A-92682/83 (Application No. 199147/82), all in the name of the present applicants, disclose and claim azino-rifamycin compounds of formula 3 H 3 BD H 3C H 3C 3 U1 0 CH 3 NH 1 0 OS H 3 as well as the corresponding oxidized quinones. Such compounds are disclosed as having strong antibacterial activity against Gram-positive and Gram-negative bacteria and especially against Mycobacterium Tuberculosis.
It is known that rifampicin is the basic rifamycin derivative worldwide used against Mycobacterium Tuberculosis. However, many other rifamycin derivatives have been discovered and patented in the past years.
The most promising of the known rifamycin derivatives, including rifampicin, have been studied and compared with each other by Jean M. Dickinson and D.A. Mitchison of the Department of Bacteriology, Royal Postgraduate Medical School of London who have concluded that the 3-(Npiperidinomethyl-azino)methylrifamycin SV (referred to herein "FCE 22250") has the most important bactericidal activity and it is the most effective sterilizing drug having also a long half- life. Such results have been published in TUBERCLE (1987) 68, 183-193.
The outstanding biological characteristics including antibacterial activity and favourable pharmacokinetic properties of FCE 22.250 on laboratory animals are reported in THE JOURNAL OF ANTIBIOTICS, Vol. 38, No. 6, pp. 779-786, June 1985. The laboratory animals were treated by an oral route and by a parenteral route, especially intravenously, with the cited drug.
Further accurate tests carried out "in vivo" by oral administration of FCE 22250 have shown that it is unsatisfactorily absorbed. This makes it unsuitable at present for practical oral administration. Also at present, no salt or ester derivatives of FCE 22250 which may be hydrolysed in the organism after absorption are known.
This problem has been taken into very careful consideration and it has been found that the bioavailability and solubility of FCE 22250 in an environment with a pH from substantially neutral to about 1 (as it is in the gastrointestinal tract of animals) are rather low. This may explain why FCE 22250 is unsatisfactorily absorbed when it is administered by the oral route.
It has now been surprisingly discovered that the oxidized (quinone) derivative of FCE 22250, which is 3-(Npiperidinomethylazino)methylrifamycin S (referred to herein as FCE 22807) is provided with a surprisingly high solubility and enhanced bioavailability compared to its reduced paregt compound (FCE 22250). This fact leads to thebelief that FCE 22807 is easily absorbed when orally administered. it is also well known that in the organs of animals (especially in the liver) there are enzymes transforming oxidized compounds into the corresponding reduced compounds and vice-versa. It is therefore possible that FCE 22807 is wholly or partially metabolized into the parent reduced compound FCE 22250.
The title compound, 3-(N-piperidinomethyl-azino)methylrifamycin S (PCE 22807) and its synthesis are described at the end of Example 1 of US-A-4, 447,432, where the compound is identified by its MS and Rf characteristics. Nothing, however, is disclosed to suggest to one skilled in the art that the oxidized (quinone) compound FCE 22807 has enhanced solubility and bioavailability compared to its parent reduced (hydroquinone) compound FCE 22250. Furthermore, no disclosure in the prior art indicates that FCE 22807 should be selected from the numerous other available rifamycins and incorporated into a pharmaceutical composition specifically for oral administration. Indeed, the very many works carried out in many Universities and laboratories throughout the world have always made use of the reduced FCE 22250 (see also IL FARMACO, May 1985, No. 5) and never of its oxidised derivative FCE 22807.
The surprisingly good solubility and bioavailability that FCE 22807 has been found to possess therefore make it possible to prepare pharmaceutical compositions comprising 3-(N-piperidinomethyl- azino)methylrifamycin S as active ingredient, suitable for oral adminstration. The present invention accordingly provides an orally adminstrable pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as active substance, 3-(N- piperidinomethyl-azino)methylrifamycin S.
The orally administrable pharmaceutical compositions of the invention comprise 3-(N-piperidinomethyl-azino) methylrifamycin S as active substance in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent). They are suitably presented in solid or liquid form.
1 The compositions are administered orally in the form of, for example, tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions. The dosage of the active ingredient depends on the age, weight and conditions of the patient, and is chosen to yield the desired activity without causing adve::se side-effects. For example, a typical effective dosage for an adult human is in the range of about 0.001 to 0. 25 ng/kg per day, preferably from 0.01 to 0.25 mg/kg per day. The compositions of the invention are therefore typically presented in unit dosage form comprising from 10 to 200 mg of active substance.
The oral formulations of the pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. The said pharmaceutical preparations may be manufactured in any known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
Solid oral forms may comprise, together with the active ingredient, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate; and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; /sweeteners; wetting agents, -such as lecithin, polysorbates, laurysulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. Liquid carriers include water, syrup, peanut oil, olive oil and the like.
The syrup may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/ or sorbitol.
The invention further provides the use of 3-(N-piperidinomethyl-azino)methylrifamycin S in the preparation of a medicament suitable for oral administration in the treatment of bacterial infection. Antibacterial activity may be exhibited against Gram-positive and Gram-negative bacteria and against Mycobacterium Tuberculosis.
The following Example illustrates the invention.
Example 1
The different solubility and instrinsic dissolution rate of FCE 22250 and FCE 22807 are reported in the following Tables 1 and 2.
TABLE 1
Solubility at 370C (after 3 hours) - mcg/ml (by HPLC method) FCE 22807 FCE22250 H 2 0 6.3 1 pH 1.2 (Chloride buffer) 168.4 1 pH 3.1 (glycine buffer) 16.6 1 pH 5.5 (acetate buffer) 6.55 1 pH 6.8 (phosphate buffer) 20.0 6.9 pH 7.4 (phosphate buffer) 58.8 34.0 Ionic strength - 0 TABLE 2
Intrinsic dissolution rate =g/CM2 -/sec FCE 22807 6.592 x 10-' FCE 2225 3.12 x 10- 5 by the Paddle method - U.S.P. XXI 300 r.p.m; T - 370C; pH 7.4 phosphate buffer; ionic strength - 0.1 Lipophilic properties of FCE 22807 and of FCE 22250 as compared with rifampicin have been also determined by chromatography in reverse phase according to the method disclosed in the literature for the Ansamycin compounds (see: IL FARRACO, Ed. Sc., 28, 298 (1973). The results (lipophilic index, stated as value of chromatographic mobility) which have been obtained are:
Rifampicin FCE 22250 FCE 22807 m -0.305 m -0.280 m -0.325 and show that the lipophilic properties of FCE 22807 are better than those of FCE 22250 and even also of rifampicin.
Claims (4)
1. An orally administrable pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as active substance, 3-(N-piperidinomethylazino)methylrifamycin S.
2. A composition according to Claim 1 in unit dosage form comprising from 10 to 200mg of the active substance.
3. A composition according to Claim 1 or 2 wherein the carrier and/or diluent comprises lactose, dextrose, saccharose, cellulose, corn starch or potato starch, silica, talc, stearic acid, magnesium or calcium stearate, a polyethylene glycol, starch, an arabic gum, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, starch, alginic acid, an alginate, sodium starch glycolate, an effervescing mixture, a dyestuff, sweetener, wetting agent, lecithin, a polysorbate, or laurylsulphate.
4. Use of 3-(N-piperidinomethyl-azino)methylrifamycin S in the preparation of a medicament suitable for oral administration in the treatment of a bacterial infection.
Published 1990 atThe Patent office. State House, 66f71 High Holborn, LondOnWC1R4TP. Further copies maybe obtainedfrom The PatentOffice. Sales Branch, St Mary Gray, Orpington, Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Gray, Kent, Con. 1187
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8905489A GB2232889B (en) | 1989-03-10 | 1989-03-10 | Oral compositions comprising 3-(n-piperdinomethylazino)methylrifamycin s |
| GB9005316A GB2229632A (en) | 1989-03-10 | 1990-03-09 | Pharmaceutical composition comprising 3-(N-piperidinomethyl-azino) methylrifamycin S as active ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8905489A GB2232889B (en) | 1989-03-10 | 1989-03-10 | Oral compositions comprising 3-(n-piperdinomethylazino)methylrifamycin s |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8905489D0 GB8905489D0 (en) | 1989-04-19 |
| GB2232889A true GB2232889A (en) | 1991-01-02 |
| GB2232889B GB2232889B (en) | 1992-12-09 |
Family
ID=10653071
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8905489A Expired - Lifetime GB2232889B (en) | 1989-03-10 | 1989-03-10 | Oral compositions comprising 3-(n-piperdinomethylazino)methylrifamycin s |
| GB9005316A Withdrawn GB2229632A (en) | 1989-03-10 | 1990-03-09 | Pharmaceutical composition comprising 3-(N-piperidinomethyl-azino) methylrifamycin S as active ingredient |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9005316A Withdrawn GB2229632A (en) | 1989-03-10 | 1990-03-09 | Pharmaceutical composition comprising 3-(N-piperidinomethyl-azino) methylrifamycin S as active ingredient |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB2232889B (en) |
-
1989
- 1989-03-10 GB GB8905489A patent/GB2232889B/en not_active Expired - Lifetime
-
1990
- 1990-03-09 GB GB9005316A patent/GB2229632A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| GB2232889B (en) | 1992-12-09 |
| GB8905489D0 (en) | 1989-04-19 |
| GB2229632A (en) | 1990-10-03 |
| GB9005316D0 (en) | 1990-05-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0366914B1 (en) | 3'-Hydroxybenzoxazinorifamycin derivative, process for preparing the same and antibacterial agent containing the same | |
| Luke et al. | Disposition of oral azithromycin in humans | |
| RU93047027A (en) | HYDROCHLORIDE, TRIAZOLYLTHIOMETHYL THIOCEPHALOSPORIN, HIS CRYSTAL HYDRATE AND METHODS FOR THEIR PRODUCTION | |
| CN101128114B (en) | 18-membered ring macrocycles and their analogs | |
| EP0548794A3 (en) | Polyaspartamide derivative as adsorbent for bile acids, polyaspartamide loaded with bile acids and preparation and use as a drug | |
| US4470980A (en) | Method of increasing oral absorption of β-lactam antibiotics | |
| Lode et al. | Comparative pharmacokinetics of new quinolones | |
| Chang et al. | Pharmacokinetics of intravenous and oral enoxacin in healthy volunteers | |
| US8747900B2 (en) | Dosage form with improved release of cefuroximaxetil | |
| US5393909A (en) | Diamine platinum complexes as antitumor agents | |
| GB2232889A (en) | Pharmaceutical composition comprising 3-(n-piperidinomethylazino)methylrifamy- cin s as active ingredient | |
| IE880503L (en) | Crystallized cephem-acid addition salts, and a process for the preparation thereof | |
| US4956373A (en) | Pharmaceutical composition comprising 3-(N-piperidinomethyl-azino) methylrifamycin S as active ingredient | |
| ES2218597T3 (en) | USE OF RIFAMYCIN DERIVATIVES FOR THE MANUFACTURE OF A MEDICINAL PRODUCT FOR THE TREATMENT OF DISEASES CAUSED BY HELICOBACTER PYLORI INFECTIONS. | |
| RU95101437A (en) | Medicinal agent containing derivatives of 3-phenylsulfonyl-3,7-diazabicyclo-[3,3,1]-nonane, method of synthesis of derivatives of 3-phenylsulfonyl-3,7-diazabicyclo-[3,3,1]-nonane | |
| Cullmann et al. | Cefetamet pivoxil: a review of its microbiology, toxicology, pharmacokinetics and clinical efficacy | |
| Archer et al. | Rifampin blood and tissue levels in patients undergoing cardiac valve surgery | |
| EP0094639B1 (en) | Sodium 7-beta-(2d-2-amino-2-carboxyethylthioacetamido)-7-alpha-methoxy-3-(1-methyl-1h-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylate heptahydrate, process for its preparation as well as pharmaceutical compositions containing same | |
| US3906107A (en) | Aminoalkyl sulfate esters with diuretic activity | |
| JPS5942315A (en) | Diarrhea therapeutical drug | |
| Seneca | Long-acting sulfonamides in urinary tract infections | |
| VilmGnyi et al. | Clarithromycin pharmacokinetics after oral administration with or without fasting in crossbred beagles | |
| US3961064A (en) | Pharmaceutical composition for remedy of hyperammoniemia | |
| EP0406811A2 (en) | Novel clathrate compounds and a drug comprising them | |
| WO1997030706A1 (en) | Composition containing antitumor agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19970310 |