CN103347863A - Improved oral targeted drug delivery system - Google Patents
Improved oral targeted drug delivery system Download PDFInfo
- Publication number
- CN103347863A CN103347863A CN2011800551776A CN201180055177A CN103347863A CN 103347863 A CN103347863 A CN 103347863A CN 2011800551776 A CN2011800551776 A CN 2011800551776A CN 201180055177 A CN201180055177 A CN 201180055177A CN 103347863 A CN103347863 A CN 103347863A
- Authority
- CN
- China
- Prior art keywords
- medicine
- delivery system
- drug delivery
- colon
- probiotic bacterium
- 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.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/745—Bifidobacteria
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
-
- 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
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K2035/11—Medicinal preparations comprising living procariotic cells
- A61K2035/115—Probiotics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Tropical Medicine & Parasitology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The present invention discloses an "Improved Oral Targetted Drug Delivery System (O-TDDS)" particularly suited for delivery of drugs having activity against the diseases located in the colon e.g. colon cancer, ulcerative colitis, protozoal infections etc. The system comprises two elements or parts viz. microspheres (drug + natural polymers such as guar gum or xanthan gum) and probiotics. Both the elements are packed together in a single, pharmaceutically acceptable oral dosage form such as a capsule. The system offers distinct advantages of drug delivery without undesirable side-effects of diarrhea, nausea or vomiting commonly encountered in case of anti-cancer drugs such as 5-Fluorouracil.
Description
Technical field
The present invention relates to field of pharmaceutical preparations.More specifically, the present invention relates to a kind of " improved oral targeted delivery of drugs system (O-TDDS) ".Described system is particularly suitable for sending having and anti-is positioned at intracolic disease, for example, and the medicine of the activity of colorectal carcinoma, ulcerative colitis, protozoan infection etc.
Background technology
The invention discloses a kind of " improved oral targeted delivery of drugs system ".This system is particularly suitable for sending having and anti-is positioned at intracolic disease, for example, and the medicine of the activity of colorectal carcinoma, ulcerative colitis, protozoan infection etc.For example, data about the antitumor and anticancer agent 5 FU 5 fluorouracil are provided.Yet this antitumor and anticancer agent is the illustrative purpose sheerly, does not have restricted.
Medicine 5 FU 5 fluorouracil (5-FU) is one of the most frequently used antitumor and anticancer agent, synthesizes first in nineteen fifty-seven (Heidelberger, C., Chaudhuri, N.K., Danneberg, P., Mooren, D., Griesbach, L., 1957.Fluorinated pyrimidines, a new class of tumor-inhibitory compounds.Nature179,663-666.).At that time, it is unique reagent with resistive connection intestines rectum cancer clinical activity.Because it is similar to natural pyrimidine structure, the 5-FU interfere RNA is synthetic, it is synthetic to suppress DNA, and finally makes the cell growth stop (Langenbach, R.J., Dancenberg, P.V., Heidelberger, C., 1972.Thymidylate synthetase:mechanism of inhibition of5-fluorouracil-2-deoxyuridylate.Biochem.Biophys.Res.Co mmun.48,1565-1571; Parker, W.B., Cheng, Y.C., 1990.Metabolism and mechanism of action of5-fluorouracil.Pharmacol.Ther.48,381-395).
At present, it is used to dissimilar malignant tumours, for example, and malignant breast tumor, head-neck malignant tumor.
The limitation of 5-FU:
Not only kill abnormal cells but also kill normal cell: as uracil analogues, it is incorporated among RNA and the DNA, and normal or unusual cells of growth are not normal fast to cause these macromole and all.Therefore, this medicine is the kill tumor cell not only, but also kills the normal cell of quick growth, comprises stomach and intestine (GI) cell and medullary cell.The shortage of this target differentiation has limited the use of this medicine.
Toxicity: structural modification, the absorption decline of nutritive substance, white corpuscle (WBC) that toxicity shows as vomiting, diarrhoea, mucomembranous cell reduce and thrombopenia.The most serious toxicity is gastrointestinal toxicity, bone marrow depression and immunotoxicity.Gastrointestinal toxicity and bone marrow depression are the dose limitation factors, hinder 5-FU and use with higher and the more effective dosage of possibility.
The GI damage: gastrointestinal damage comprises that stomatitis, diarrhoea, fine hair expose, destroy the mucous membrane integrity, intestinal permeability increases and enteron aisle enzyme such as kinase whose active decline of chest glucoside.It is reported, because the cytotoxic effect of the mucous membrane of 5-FU, it can cause mucositis (Mahood when giving via parenteral and intraperitoneal approach, D.J., Dose, A.M., Loprinzi, C.L., 1991.Inhibition of5-fluorouracil-induced mucositis by oral cryotherapy.J.Clin.Oncol.9,449-452 and Pico, J.L., Avila-Garavito, A., Naccache P., 1998.Mucositis:its occurrence, consequences, and treatment in the oncology setting.Oncologist3,446-451).
The micropopulation disorder: the eubiosis of normal microflora is given 5-FU by whole body and upsets.This causes the change of normal microflora, and this change causes some complication and multiple organ failure again.This is with bacterium displacement and diarrhoea.In addition, the bacterium in the enteron aisle is changed gram (-) ve bacterium into by gram (+) ve bacterium, increases the chance of secondary infection.
Existing 5-FU preparation and limitation thereof
The existing 5-FU preparation that can buy on the market comprises injection (parenteral) or capsule (oral).Yet these two kinds of existing preparations all are subjected to following restriction:
The parenteral approach:
Because cytotoxicity has side effect widely.Except cancer cells, this also influences normal cell.Because medicine is directly released in the blood flow, have no idea to avoid it to contact and alleviate side effect with Normocellular.
Oral route:
The oral absorption of form of all right capsule of medicine.Yet, although preparation can obtain and in theory the prediction patient's compliance better, said preparation also is out of favour.Key constraints is irregular drug release characteristics (profile) and adverse side effect, for example, suffer from diarrhoea and the GI that causes having blood in stool hemorrhage.The extensive difference of unpredictable release, curative effect and also have adverse side effect to cause the clinician to rely on parenteral formulation is although parenteral formulation has its limitation and side effect.
Overcome the limitation of oral route
The innovative approach of the problem of a kind of adverse side effect that overcomes oral preparations and unpredictable release characteristics thereof is exploitation colorectum targeted delivery of drugs system.A kind of like this Innovation System of the prior art below is discussed.
The colorectum targeted orally administered pharmaceutical delivery system of disclosed innovation in the prior art
In the prior art, review article (Sinha and Kumria, 2001:Polysaccharides in colon-specific drug delivery, International Journal of Pharmaceutics224pp.19-38) a kind of like this Innovation System is disclosed in.It belongs to colorectum targeted orally administered pharmaceutical delivery system.It is at " core " employing " natural polymer layer " of medicine, i.e. sheet in the sheet.Core is made up of the medicine 5 FU 5 fluorouracil, and outside dressing is by only being formed by the natural polymer of colonic bacterial digestion such as guar gum.When the digestion tablet, the medicine 5 FU 5 fluorouracil does not discharge in stomach or small intestine, because its natural polymer " protection dressing " can not be digested.Yet when it arrived colon, this natural polymerization dressing of the specific bacterial digestion of colonic caused medicine only in colonic " target release ".
Owing to discharge at the colonic target, the prior art targeted delivery systems of the Ti Chuing advantage that less side effect is provided in theory and treated characteristic (profile) preferably thus.Yet, when estimating this system, the inventor finds that there is following critical limitations in this system:
Does this system work behind first dosage? this system is based upon on the following hypothesis: target release meeting causes drug release at colonic because the colon micropopulation can help to digest 5-FU tablet " polymeric layer ".Its hypothesis colon micropopulation can not be subjected to the influence of the medicine of colonic release, and has only cancer cells to be affected.Yet if the medicine that colonic discharges is affected micropopulation or makes the micropopulation loss of activity, the targeted delivery of drugs system will lose efficacy and no longer work so.When taking the targeted delivery of drugs system of next dosage, behind the arrival colon, polymeric layer can not digested by the colon micropopulation because of the damage that first dosage brings.This can cause colorectum targeted delivery of drugs thrashing.This is the reason that the contriver worries, because just can't obtain the information of this respect known to the contriver in the prior art.
The problem that the contriver faces is:
Does 1, they influence the worry whether rationally (genuine) of " drug release characteristics " of natural polymer base drug delivery system (wherein the colon micropopulation plays key and function) to 5-FU?
2, influence the colon micropopulation really at 5-FU and also move therefrom under the situation of natural polymer base targeted delivery of drugs system, how to address this problem? do you how to guarantee the functional unaffected of delivery system?
Therefore, the challenge that faces of present inventor is how to develop a kind of at every turn all can working and the firm targeted delivery of drugs system that can not lose efficacy.The present inventor has attempted several different methods, has finally successfully developed a kind of improved oral targeted delivery of drugs system, is particularly suitable for sending the colon-specific medicine and such as antitumor and anticancer agents such as 5 FU 5 fluorouracils, has overcome the defective of prior art system.
Summary of the invention
Goal of the invention
The objective of the invention is to disclose a kind of improved oral targeted delivery of drugs system, be particularly suitable for sending having and anti-ly be positioned at intracolic disease, for example, the medicine of the activity of colorectal carcinoma, ulcerative colitis, protozoan infection etc.
Another object of the present invention is to disclose a kind of improved oral targeted delivery of drugs system for single, pharmaceutically acceptable formulation such as capsule, and this system comprises the unique combination of microballoon (medicine+natural polymer) and probiotic bacterium.
Still a further object of the present invention is to disclose a kind of improved oral targeted delivery of drugs system for cancer therapy drug such as 5-FU, and wherein, drug-induced adverse side effect is namely suffered from diarrhoea, vomits, lost weight, alopecia etc. significantly reduces or be eliminated together.
Also having another purpose is to disclose a kind of oral pharmaceutical delivery system, wherein by using probiotic bacterium to overcome the negative effect of medicine to micropopulation in the target area with a kind of innovation mode.
A purpose is to disclose a kind of improved oral pharmaceutical delivery system again, and wherein the limitation of prior art and defective are overcome.
Description of drawings
Do not have
Embodiment
The invention key element: delivery system of the present invention comprises two kinds of moietys that are packaged into single, pharmaceutically acceptable oral dosage form such as capsule.Described two kinds of moietys are:
1. microballoon: they are formed by active medicine 5-FU with such as natural polymers such as guar gum and xanthan gum.
2. probiotic bacterium: they are the suitable probiotic bacterium of spraying drying, lyophilized powder form, for example, and bifidus bacillus class (bifidobacterium bifidum, bifidus longum bb etc.).
Test this system animal (rat), found to have obtained fabulous result.Solved following two basic problems in present inventor's brains so as scheduled:
Does 1, they influence the worry whether rationally (genuine) of " drug release characteristics " of natural polymer base drug delivery system (wherein the colon micropopulation plays key and function) to 5-FU?
2, influence the colon micropopulation really at 5-FU and also move therefrom under the situation of natural polymer base targeted delivery of drugs system, how to address this problem? do you how to guarantee the functional unaffected of delivery system?
Meaning: because colon bacteria plays key and function in natural polymer base drug delivery system, therefore be necessary to minimize the negative effect of the micropopulation of 5-FU, and if possible, then eliminate this negative effect fully.Otherwise in case medicine kill microorganisms group (bacterium), this system will can not work after the first time again, because the outside dressing of natural gum can not digested.
The present situation of prior art: the eubiosis of normal intestinal microbiota is upset in the whole body administration of known 5-FU in the prior art, this may cause diarrhoea and other complication (Gutheli again, J.C., Kearns, C.M. (Eds), 2008.Gastrointestinal complication of chemotherapy in M.C.The Chemotherapy Source Book, Lippinicott Williams﹠amp; Wilkins, USA, pp.197-208).The inhibition of the normal microflora of 5-FU can cause the field planting drag of the born resistant microorganism (as difficult clostridium) of preexist among the GIT to descend with follow-up hypertrophy.
Yet, still undocumentedly in the prior art be " whether 5-FU can influence specified microorganisms/micropopulation related in the digestive process of natural gum, thus the release of influence " natural gum base " drug delivery system? "The inventor finds, is that this aspect is not resolved in the prior art astoundingly at all, and does not still have experimental evidence or data in this respect.
Challenge: the associated viscera that should mention is here, only the colon micropopulation of the polysaccharide metabolizing bacteria of particular type (being responsible for discharging medicine from coating tablet) and high complexity is separated and estimate it the susceptibility of 5-FU is actually infeasible.Must design a kind of suitable Bioexperiment system, the release characteristics that whether cancer therapy drug such as 5-FU is influenced natural gum base drug delivery system provides clear and definite technical evidence with innovating.
Experimental technique
This experimental technique relates to external and the interior two kinds of researchs of body.These researchs lay particular emphasis on two aspects:
Whether a evaluation cancer therapy drug such as 5-FU influence the release characteristics of natural gum base drug delivery system.
B shows and a kind ofly overcomes medicine to the practical strategies of the negative effect of micropopulation if any.
In order to answer the problems referred to above, the inventor has adopted a kind of use to comprise the innovative experiment method of rat " lived biosystem ".All experimentations have all obtained the approval of animal Ethics Committee of mechanism, referring to authentication code 954/ac/06/CPCSEA/09/19.To the research that experimentizes of 30 Wister albefaction rats.
Animal is divided into 6 groups, 5 every group.Give the oral dosage shown in the following table 1 to every animal in the group.
Table 1: to the processing of animal (Wister albefaction rat) and the dosage that gives
| Sequence number | Group | Handle | 5-FU dosage (oral at every turn) |
| 1. | Group I | The microballoon that has only xanthan gum and guar gum | 8mg/ days |
| 2. | Group II | The 5-FU powder | 8mg/ days |
| 3. | Group III | 5-FU microballoon (50% charge capacity among the 16mg) | 8mg/ days |
| 4. | Group IV | Probiotic bacterium | 1g/ days |
| 5. | Group V | 5-FU powder and probiotic bacterium | 8mg/ days+1g/ days |
| 6. | Group VI | 5-FU microballoon and probiotic bacterium | 8mg/ days+1g/ days |
Every day is by the existing dose out powders that suspends in milk.These medicaments are irritated the administration of stomach pin by per os and are carried out contacting with follow-up the first time, continue five days at every turn, are spaced apart 20 days.
Experimental technique A: humanity is put to death from 2 animals in each group, and cecal content is collected in the sterile petri dish, is used for stripping research immediately.For stripping research, use 5-FU and the compression coated tablets of natural gum and the microballoon of 5-FU and natural gum.Experimentize in the beaker of the 250ml that in jar water that contains of dissolution test device, floods.Preliminary research is the HCl(pH1.2 at the 0.1N of 150ml) in carry out 2h.After this, in dissolution medium, add NaOH, with pH regulator to 6.8.Be that 6.8 phosphate buffered saline buffer is added 200ml with volume with pH.After this research continues to carry out 3 hours, add cecal content (4%w/v).Carry out the stripping in the cecal content medium, up to finishing 24 hours.Result of study provides in following table 2:
Table 2: per os gives the cecal content of rat of 5-FU to the influence of the drug release characteristics of oral targeted delivery of drugs system
From the experiment of carrying out, obtain following answer:
5-FU has destroyed the related micropopulation of release from the medicine of " natural gum base " delivery system significantly: the cecal content with 5-FU powder or 5-FU microballoon rat feeding does not contain the microorganism with enough activity.Below fact proved this point: when the basic drug delivery system of natural natural gum (compression coated tablets/microballoon) contacts with the content of above-mentioned rat, with rat wherein not per os give that 83-92% compares in the contrast of any medicine, drug release significantly reduces, and is 41%-54%.This shows that per os feeds " micropopulation " of rat of 5-FU by " destructions ", because related these micropopulations just (bacterium) in the natural gum in digesting " targeted delivery of drugs system ".Because the release of medicine is extremely few compared with the control, this shows that medicine has killed bacterium really.
Therefore, answered first problem in inventor's brains for certain, namely " whether they influence the worry of " drug release characteristics " of natural polymer base drug delivery system (wherein the colon micropopulation plays key and function) to 5-FU reasonable? "
Yes, micropopulation has been subjected to influence really, and this has had influence on " drug release characteristics " of natural gum base drug delivery system, because there is not the micropopulation of sufficient amount to digest " natural gum ".
This shows that the medicine (not only segmented intestine targeted form, and conventionally form) with antimicrobial acivity has all influenced colon bacteria unfriendly.Therefore, " targeted delivery of drugs system " success technically based on natural gum, because they functional is based upon on the integrity of micropopulation, if and the patient takes microbiotic or any other influences the medicine of micropopulation, keep the integrity of micropopulation in fact very difficult.
Since the inventor can prove that " colon micropopulation " has been subjected to the influence of medicine really and " drug release " of segmented intestine targeted drug delivery system also significantly reduces, so just must answer second problem, namely " influence the colon micropopulation really and move therefrom under the situation of natural polymer base targeted delivery of drugs system at colonic drug such as 5-FU, how to address this problem? how to guarantee the functional unaffected of delivery system? "
Behind the research and various experimental technique that continue, the inventor adopts two kinds of technology interventions to solve the problems referred to above with a kind of practical way of innovation.
I)
Replace independent powder type to experimental animal with the microspheres form that comprises " medicine+natural gum " Give 5-FU
Not the 5-FU that gives activity form to experimental animal, but comprise the microballoon (details of preparation microballoon formally provides) of the mixture of 5-FU and natural polymerization natural gum (being guar gum and xanthan gum) in table 4.Therefore, compared by the prior art of 5-FU tablet with the natural polymer bag with wherein open, the inventor uses is the natural polymer base microballoon of undocumented 5-FU still in the prior art.The use of attempting microballoon is because following two reasons: the first, in order to improve " dispersion of medicine " in the colon, thereby make it possible to reduce the adverse side effect that discharges the position.Experimental evidence has proved with the 5-FU powder and has compared that the use of microballoon has reduced side effect significantly.The second, in order to simplify manufacturing process and needing to avoid any special machinery.Different with " sheet in the sheet " delivery system of the prior art of the special machinery of needs, " microballoon base delivery system " of the present invention without any need for special machinery, and easily the manufacture scale batch.
The ii) co-administered of commercially available probiotic bacterium and 5-FU microballoon
For " mitigation " is subjected to the colon micropopulation that 5-FU damages, whether the co-administered that the inventor has estimated probiotic bacterium and drug delivery system can have " supply " effect to the colon micropopulation that sustains damage/lose because of medicine " chemical attack ".Give experimental animal (albefaction Wister rat) jointly with the bifidus bacillus class (bifidobacterium bifidum and bifidus longum bb) of commercially available powder type and the microballoon of 5-FU.Be that the probiotic bacterium of 1g and 5-FU microballoon that dosage be 8mg/ animal/sky jointly give every animal with dosage every day.Whether the negative side-effects of confirming the internal intestinal microbiota of microballoon of 5-FU thus can overcoming by probiotic bacterium jointly.The result provides in following table 3.
Table 3: per os gives the cecal content of rat of 5-FU and probiotic bacterium to the influence of the drug release characteristics of oral targeted delivery of drugs system
Prerequisite: the method that the inventor adopts is based upon on the following prerequisite: if " micropopulation " of colon is considered as single " unit " and this unit can be avoided the 5-FU damage to a certain extent, the polysaccharide metabolizing bacteria of being responsible for discharging the particular type of medicine so from coating tablet also will be protected automatically.This can cause colon microorganism wherein to play the success of any " natural polymer base " segmented intestine targeted drug delivery system of crucial and function.
The experimental technique that adopts and the result who obtains: when experimentizing test, the result who obtains shows that this idea is correct (table 3).With during the cecal content of feeding separately the rat of 5-FU contact, drug release only is 41.56% at microballoon, and with microballoon that the cecal content of the rat of nursing 5-FU+ probiotic bacterium contacts in, drug release increases greatly, is 92.32%.
Understand: the co-administered of probiotic bacterium can help almost completely to overcome medicine to the disadvantageous effect of micropopulation.Below fact proved this point: the vitro drug release (92.32%) of the microballoon that contact with the cecal content of the rat of feeding the 5-FU+ probiotic bacterium and wherein animal not give the drug release (92-94%) of the contrast of any medicine extremely approaching.Therefore the result of above-mentioned research provides the first direct experiment evidence of relevant following two aspects:
1. colonic drug such as 5-FU have influenced the internal organ micropopulation unfriendly: therefore, the fault that can not get rid of the targeted delivery of drugs system that uses natural polymer is because functional basis of such " natural polymer base targeted drug delivery system " integrity of colon micropopulation just.
2. can overcome the damage to micropopulation: the damage to the colon micropopulation can overcome by giving suitable probiotic bacterium jointly.
To adopt " innovative approach " of the present invention whether can reduce or eliminate the unnecessary side effect of colonic drug in order solving, as diarrhoea, alopecia etc., to use 5-FU to test animal (rat) as " typical case ".Provide result of study below:
Unnecessary side effect about the oral administration of 5-FU powder
The lasting albefaction Wister rat that gave 5-FU powder (8mg/ days) in 5 days is lost hair or feathers, is lost weight and the bloody diarrhea by the inspection of putting to death the cecal content that obtains behind the animal is reflected.The histopathological examination of colon demonstrates ulcer and loses epithelial lining.Diarrhoea appears in animal and mucositis shows the complete multilated of colon micropopulation.
Unnecessary side effect about the oral administration of 5-FU microballoon
The parallel study of " natural polymer " basic microballoon (targeted delivery of drugs system) of use 5-FU discloses with the 5-FU powder to be compared, although side effect has reduced, does not eliminate, and this disorder that shows micropopulation is taking place.Occurred losing weight and suffering from diarrhoea though give the rat of the 5-FU microballoon of polymer coating, do not lost hair or feathers.Yet, by not having bloodstain in the cecal content of putting to death the animal acquisition.The histopathological examination of colon has only disclosed focal ulcer (focal ulcerations).This with give the 5-FU powder, observed with the group of the diffusivity ulcer of the mucous membrane of colon that loses epithelial lining opposite.
Unnecessary side effect about the oral administration of 5-FU microballoon+probiotic bacterium
The co-administered of probiotic bacterium and 5-FU microballoon has been eliminated the negative side-effects of medicine fully, and has protected " the colon micropopulation " of experimental animal significantly.Following observations has proved this point:
I) do not suffer from diarrhoea, and the colon/cecal content of experimental animal is normal at all
Ii) experimental animal is alleviated by any weight, and their body weight to compare with control animal be the same
Iii) to have disclosed mucous membrane and the placenta percreta of colon normal for the histopathological examination of the colon of experimental animal, and epithelial lining is without any loss.
Therefore the present invention indicates and a following relevant weight break point:
A. the successful performance of targeted delivery of drugs system: more specifically, it is by overcoming " defective " in the prior art system, the verified success of using " the oral colon-target drug delivery system " of natural polysaccharide method.It discloses prior art " based on the segmented intestine targeted drug delivery system of natural polymer method " first is defective technically.After taking in first dosage, the drug release of said system can seriously suffer damage (compromised), because medicine can influence related micropopulation in " based on the medicine delivery system of natural polymer functional ".These micropopulations have digested the outside natural polymer dressing of targeted delivery of drugs system just, have caused the release of medicine.If their own d/d medicines kill, then dressing can not digested when taking in next dosage, and system can lose efficacy.This limitation has been obtained confirmation by experiment by the contriver, and is overcome with a kind of innovation mode by the co-administered of probiotic bacterium.Only be that 41.56% prior art system is compared with drug release wherein, the drug release in the system of the present invention is 92.32%(table 3).
Significantly reducing of the adverse side effect of the medicine of b target colon: the detrimentally affect of segmented intestine targeted medicine such as cancer therapy drug (for example 5-FU) can be astoundingly overcomes by " microballoon " form of using itself and natural gum and the co-administered of going back profitable probliotics.This has been obtained confirmation by the inventor by experiment on a kind of animal model (rat).The animal that probiotic bacterium and cancer therapy drug 5-FU give does not jointly suffer bloody diarrhea and lose weight/lose hair or feathers, and does not give the detrimentally affect that the animal of probiotic bacterium suffers bloody diarrhea and loses weight and lose hair or feathers.
Table 4: the preparation method-emulsion polymerization technology of the 5-FU microballoon of natural polymer bag quilt
Novelty of the present invention aspect
Known to the inventor, comprise microballoon (mixture of medicine+natural polymer (as guar gum and xanthan gum)) and probiotic bacterium combination, be used for sending colon-specific medicine and antitumor and anticancer agent such as 5 FU 5 fluorouracil, be the improved oral targeted delivery of drugs system (O-TDDS) of single pharmaceutically acceptable oral dosage form such as capsule disclosing Anywhere in prior art not as yet.Therefore it has novelty.
Creative
Therefore, it is a kind of be used to the improved oral targeted delivery of drugs system of sending colon-specific medicine and antitumor and anticancer agent such as 5 FU 5 fluorouracil that creativeness is that the inventor has successfully developed, this system comprises the combination of microballoon (mixture of medicine+natural polymer (as guar gum and xanthan gum)) and probiotic bacterium, is single pharmaceutically acceptable oral dosage form such as capsule.With respect to existing knowledge, it has significant technical progress.
In addition, creativeness has been to eliminate fully the negative side-effects of medicine (for example 5-FU) to the colon micropopulation.In the prior art, because the problem that 5-FU influence micropopulation is not resolved, wherein there is defective technically in micropopulation such targeted drug delivery system of playing key and function, and the possibility of inefficacy is very big.In case this is because micropopulation not normal (upset), next formulation can be inoperative because the natural polymer dressing for want of colon bacteria digest it and can not open.This problem is resolved in the present invention.
Industrial application
The invention discloses a kind of improved oral targeted delivery of drugs system, be particularly suitable for sending and have the anti-medicine that is positioned at the activity of intracolic disease (as colorectal carcinoma, ulcerative colitis, protozoan infection etc.).
This system can be easily with industrial-scale production, because this system uses the ready-made component that obtains easily.Production and scale are so simple, are conducive to industrial application.
Advantage of the present invention
1. side effect significantly reduces
2. patient's compliance is better
3. the treatment characteristic is better
4. compactness and effectively formulation
5. the economy of production aspect
Disclosed concept can be extrapolated on the other drug well among the present invention.It can be used for reducing with natural gum/polymkeric substance brings side effect in the delivery system of " targeted delivery ".Below, provide the combination of using natural gum such as guar gum and xanthan gum in table 5 and the table 6 respectively, or used the example of medicine of such target colon of guar gum separately.
Table 5: the medicine of the target colon of the combination of use guar gum and xanthan gum
Table 6: guar gum base colon-specific preparation
| Sequence number | The medicine that uses | Sequence number | ? |
| 1. | Budesonide/dexamethasone | 12. | Ornidazole |
| 2. | Dexamethasone | 13. | Metoprolol tartrate |
| 3. | Albendazole | 14. | Theophylline |
| 4. | Indomethacin | 15. | Mesalazine |
| 5. | Technetium-99m-DTPA | 16. | The cassia angustifolia glucoside |
| 6. | 5-ASA | 17. | Rofecoxib |
| 7. | Mebendazole | 18. | Methotrexate |
| 8. | Albendazole/tinidazole | 19. | Diltiazem hydrochloride |
| 9. | Celecoxib | ? | ? |
| 10. | 5 FU 5 fluorouracil | ? | ? |
| 11. | Trimetazidine Hydrochloride | ? | ? |
Keep the globality of enteron aisle/colon micropopulation and the practical mechanism of integrity when therefore, the present invention has successfully showed a kind of " chemical attack " of the colon-specific medicine of listing in the table 6 on facing.Because the method for using among the present invention relates generally to the use of microballoon of the medicine+probiotic bacterium of " being packaged into " single pharmaceutically acceptable oral dosage form, the example of the 5-FU that provides does not have restricted, but can be considered a kind of illustrative example of explaining the present invention better and promoting the understanding of the present invention.
In case understood disclosed innovation concept among the present invention, those skilled in the art can realize embodiments of the present invention, version and easily to its improvement, for example:
-several drugs+single probiotic bacterium: be not single medicine, but the combination of multiple medicine can be used with single probiotic bacterium.
-different pharmaceutical: the disclosed medicine, delivery system can use any suitable medicine in the application.
-multiple medicine+different probiotic bacteriums: in the application, the disclosed probiotic bacterium, can use any other probiotic bacterium.
-single medicine+multiple probiotic bacterium: in system, can use more than a kind of probiotic bacterium;
-multiple medicine+multiple probiotic bacterium: can use the combination of more than a kind of medicine and more than a kind of probiotic bacterium.
Therefore, any such embodiment, version or improvement all should be considered as within the scope of the invention.
Claims (according to the modification of the 19th of treaty)
1. improved oral colon-target drug delivery system comprises mixture and pulverous probiotic bacterium of medicine and the natural polymer of microspheres form,
Wherein
Probiotic bacterium in the-described targeted delivery systems is particular type and exists with specific quantity, as the part of fundamental sum key, be used in the face of keeping globality and the integrity of enteron aisle/colon micropopulation after taking in first oral preparation during by colon-specific medicine " chemical attack "
-be stable by the drug release of this system
Micropopulation environment in-this system protection body, and the bacterial flora that sufficient amount is provided is used for stable drug release to digest the natural polymer dressing of described drug delivery system
Three kinds of compositions of all of-described system, i.e. " live bacterium " of medicine, polymkeric substance and probiotic bacterium form is packaged into single, acceptable oral dosage form pharmaceutically together.
2. the described drug delivery system of claim 1, wherein, the specific quantity of described probiotic bacterium refers to medicine: the ratio of probiotic bacterium is about 1:125.
3. the described drug delivery system of claim 1, wherein, the described probiotic bacterium that exists in the described system is the bifidus bacillus class.
4. the described drug delivery system of claim 1, wherein, described probiotic bacterium is bifidobacterium bifidum and bifidus longum bb.
5. the described drug delivery system of claim 1, wherein, described medicine is any medicine that is selected from the group that comprises following compound: known anticancer compound such as 5 FU 5 fluorouracil or any other anticancer compound.
6. the described drug delivery system of claim 1, wherein, described medicine is to be selected from any medicine that comprises such as in the group of following colon-specific compound: budesonide/dexamethasone, dexamethasone, albendazole, indomethacin, 5-ASA, mebendazole, albendazole/tinidazole, celecoxib, Trimetazidine Hydrochloride, ornidazole, metoprolol tartrate, theophylline, mesalazine, anthraglucosennin, rofecoxib and methotrexate.
7. the described drug delivery system of claim 1, wherein, described medicine is the antitumor and anticancer agent 5 FU 5 fluorouracil.
8. the described drug delivery system of claim 1, wherein, described natural polymer is natural gum as guar gum or xanthan gum or any other natural polymer.
9. improved oral targeted delivery of drugs system, its detailed description as the 11st page of the 9th to 19 row of reference the application, the 12nd page of the 8th to 17 row and the 14th page of the 2nd to 3 row is described in fact in this article.
Illustrate or state (according to the modification of the 19th of treaty)
Statement according to PCT the 19th (1) bar, the 46th modification of PCT detailed rules and regulations
Below declare and understand the details of revising in the claim of submitting in the international stage.
Revise reason: in view of the examination reports that ISA/US does about creativeness, carry out following modification in the Re of its WO Item V.
Revise:
Replace the claim 1 to 7 of pending trial with amended claim 1 to 9.
Explanation:
The applicant thanks the auditor to accept novelty of the present invention and industrial use and does not have any dispute.The applicant advocates that in all seriousness creativeness of the present invention is to disclose a kind of Innovation System, and wherein probiotic bacterium is impregnated in the function and the key component that successfully work aspect the stable release medicine as being used for drug delivery system.(active medicine: the ratio of probiotic bacterium is about 1:125 to the probiotic bacterium of particular type (bifidus bacillus class) with particular concentration; Referring to 8mg5-FU and 1000mg probiotic bacterium in the 6th page table 1) be impregnated in this system.
Explain as following, this little, simple and step that have a novelty is guaranteed the stable release of medicine after taking in first oral preparation, and overcome the major technique limitation of prior art delivery system:
The applicant agrees auditor's following viewpoint: known probiotic bacterium digestion polymkeric substance, and this is that they have been used in drug delivery system (US6319518B1(Lee etc.)) and Review(Kumar) in reason.Yet the key component of missing in the prior art is to lack opening of tablet in the targeted delivery of drugs system depended on that micropopulation is to the understanding of the digestion of polymeric coatings or even understanding.If after taking in first tablet and discharging medicine, micropopulation is killed, how is next tablet opened?
Documents does not all disclose ' technology ' exploitation that the knowledge of medicine, natural polymer or probiotic bacterium is used for ' targeted delivery systems ' form that the present invention discloses.The applicant respectfully advocates, identification problem (how second tablet is opened behind the first tablet kill microorganisms group) and to make solution (add " bacterium that lives " of certain content and particular type, checking and proof " concept works " subsequently experimentize) be ' link of disappearance ' that the present inventor assert and overcomes.From any prior art file, lack any discussion or elaboration about this respect fully, this is that non-obvious this fact is clearly to those skilled in the art, although functional bacterium ' digestion ' natural polymer that depends on of drug delivery system, and if these bacteriums ' death ' system can lose efficacy.
With documents (that is: Lee etc.; Kuma and Moger) compare outstanding creationary difference technical characterictic of the present invention:
● as the probiotic bacterium of key and the funtion part of drug delivery system:
Probiotic bacterium (specific type and with medicine with particular concentration) in a particular manner is impregnated in to guarantee that as key and the funtion part of drug delivery system this system successfully works.
● by the concrete external and zooscopy the finished proof to Proof of Concept: the prior art file is all discussed the concept relevant with the concept of ' drug delivery system can lose efficacy ' behind absorption first tablet or is provided at any ' Proof of Concept ' of experimental data aspect, because micropopulation can be killed, thereby there are not enough micropopulations to have to digest ' polymeric coatings ' of next tablet.On the contrary, the applicant has successfully proved ' Proof of Concept ' relevant with the problems referred to above, and to have showed solution with external testing data form in the body.
Therefore, the disclosed content relevant with medicine, polymkeric substance or probiotic bacterium is different fully in the present invention and the prior art, also just not talkative the present invention by the disclosure content expectation to.
The effect of revising
By above-mentioned explanation and modification, creative feature of the present invention has obtained fully outstanding, and is introduced in claims.It seems that now the present invention meets creationary standard.
Claims (7)
1. an improved oral targeted delivery of drugs system (O-TDDS), wherein, described drug delivery system comprises two kinds of moietys, that is:
I. microballoon, it is the mixture of medicine and natural polymer;
Ii. the probiotic bacterium of powder type,
That described two kinds of moietys are packaged into together is single, pharmaceutically acceptable oral dosage form such as capsule.
2. the described drug delivery system of claim 1, wherein, described medicine is any medicine that is selected from the group that comprises following compound: known anticancer compound such as 5 FU 5 fluorouracil or any other anticancer compound.
3. the described drug delivery system of claim 1, wherein, described medicine is to be selected from any medicine that comprises such as in the group of following colon-specific compound: budesonide/dexamethasone, dexamethasone, albendazole, indomethacin, 5-ASA, mebendazole, albendazole/tinidazole, celecoxib, Trimetazidine Hydrochloride, ornidazole, metoprolol tartrate, theophylline, mesalazine, anthraglucosennin, rofecoxib and methotrexate.
4. the described drug delivery system of claim 1, wherein, described medicine is the antitumor and anticancer agent 5 FU 5 fluorouracil.
5. the described drug delivery system of claim 1, wherein, described natural polymer is natural gum as guar gum or xanthan gum or any other natural polymer.
6. the described drug delivery system of claim 1, wherein, described probiotic bacterium is any suitable probiotic bacterium, includes but not limited to the bifidus bacillus class, for example, bifidobacterium bifidum and bifidus longum bb.
7. improved oral targeted delivery of drugs system, wherein, it is as being described in the description in fact of institute herein with reference to detailed.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2220DE2010 | 2010-09-17 | ||
| IN2220/DEL/2010 | 2010-09-17 | ||
| PCT/IN2011/000642 WO2012035561A2 (en) | 2010-09-17 | 2011-09-19 | Improved oral targetted drug delivery system |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103347863A true CN103347863A (en) | 2013-10-09 |
Family
ID=45832028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011800551776A Pending CN103347863A (en) | 2010-09-17 | 2011-09-19 | Improved oral targeted drug delivery system |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2632902A4 (en) |
| JP (1) | JP2013537221A (en) |
| CN (1) | CN103347863A (en) |
| WO (1) | WO2012035561A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653341A (en) * | 2018-05-30 | 2018-10-16 | 华中科技大学 | A kind of medicine box and its application for malignant tumour immunization therapy |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102871983B (en) * | 2012-10-31 | 2015-12-09 | 中国人民解放军第四军医大学 | Gamlogic acid conlon targeting controlled release tablet and preparation method thereof |
| CN103142494B (en) * | 2013-03-19 | 2018-06-26 | 河北凯盛医药科技有限公司 | Ornidazole oral preparation and preparation method thereof |
| RU2554739C1 (en) * | 2014-03-25 | 2015-06-27 | Александр Александрович Кролевец | Method of obtaining albendazole nanocapsules |
| JP2017088540A (en) * | 2015-11-10 | 2017-05-25 | ビオフェルミン製薬株式会社 | Prophylactic and/or therapeutic agent for 5-fluorouracil-induced bowel disease |
| CN105997937A (en) * | 2016-07-04 | 2016-10-12 | 中北大学 | Preparation method of 5-fluorouracil imprinted gel microspheres |
| WO2018039087A1 (en) * | 2016-08-20 | 2018-03-01 | Gregg John Malcolm Hall | Antimicrobial drug methods of use & therapeutic compositions |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6319518B1 (en) * | 1997-07-03 | 2001-11-20 | Samyang Corporation | Colon selective drug delivery composition |
| CN1596124A (en) * | 2001-09-28 | 2005-03-16 | 纽特休迪克斯公司 | Delivery system for biological component |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AUPQ132599A0 (en) * | 1999-07-01 | 1999-07-22 | Commonwealth Scientific And Industrial Research Organisation | Nasogastric enteral formulations |
| US20070098784A1 (en) * | 2001-09-28 | 2007-05-03 | Nutraceutix, Inc. | Delivery system for biological component |
| US20050266069A1 (en) * | 2002-09-06 | 2005-12-01 | Simmons Donald L | Stable probiotic microsphere compositions and their methods of preparation |
-
2011
- 2011-09-19 CN CN2011800551776A patent/CN103347863A/en active Pending
- 2011-09-19 EP EP11824692.5A patent/EP2632902A4/en not_active Withdrawn
- 2011-09-19 JP JP2013528836A patent/JP2013537221A/en active Pending
- 2011-09-19 WO PCT/IN2011/000642 patent/WO2012035561A2/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6319518B1 (en) * | 1997-07-03 | 2001-11-20 | Samyang Corporation | Colon selective drug delivery composition |
| CN1596124A (en) * | 2001-09-28 | 2005-03-16 | 纽特休迪克斯公司 | Delivery system for biological component |
Non-Patent Citations (6)
| Title |
|---|
| M.K. CHOURASIA等: "Potential of Guar Gum Microspheres for Target Specific Drug Release to Colon", 《JOURNAL OF DRUG TARGETING》 * |
| RAVI KUMAR等: "Polysaccharides Based Colon Specific Drug delivery: A Review", 《INTERNATIONAL JOURNAL OF PHARMTECH RESEARCH》 * |
| V.R. SINHA等: "Colonic drug delivery of 5-fluorouracil: an in vitro evaluation", 《INTERNATIONAL JOURNAL OF PHARMCEYTICS》 * |
| 梅旭辉，等: "《食品药品化妆品监督管理大全》", 1 June 2004, 湖北科学技术出版社 * |
| 熊德鑫，等: "《肠道微生态制剂与消化道疾病的防治》", 1 August 2008, 科学出版社 * |
| 郭兴华，等: "《益生菌基础与应用》", 31 October 2002, 北京科技出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653341A (en) * | 2018-05-30 | 2018-10-16 | 华中科技大学 | A kind of medicine box and its application for malignant tumour immunization therapy |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012035561A3 (en) | 2012-07-19 |
| EP2632902A2 (en) | 2013-09-04 |
| JP2013537221A (en) | 2013-09-30 |
| WO2012035561A2 (en) | 2012-03-22 |
| WO2012035561A4 (en) | 2012-08-16 |
| EP2632902A4 (en) | 2014-05-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103347863A (en) | Improved oral targeted drug delivery system | |
| US10449194B2 (en) | Formulations of 5-fluorocytosine and uses thereof | |
| CN103442710B (en) | The combination of 1 inhibitor of test point kinases and WEE1 kinase inhibitors | |
| KR102211832B1 (en) | Composition containing nicotinic acid and/or nicotinamide and/or tryptophan for positively influencing the intestinal microbiota | |
| AU2010257400B2 (en) | Co-administration of polysaccharide with a chemotherapeutic agent for the treatment of cancer | |
| Azehaf et al. | Microbiota-sensitive drug delivery systems based on natural polysaccharides for colon targeting | |
| CN109620828A (en) | Method for establishing model, model and the application of chemotherapy metenteron adverse reaction | |
| US20160243034A1 (en) | Pharmaceutical composition comprising capecitabine and cyclophosphamide | |
| CN110662533A (en) | Methods and compositions for delivering mycophenolic acid active agents to non-human mammals | |
| JPS6365653B2 (en) | ||
| US20140154312A1 (en) | Oral targetted drug delivery system | |
| JP2021536491A (en) | Drug release control dosage form | |
| CN109771437B (en) | Application of trifluorothymidine in preparing medicine for treating triple negative breast cancer | |
| US12011469B2 (en) | Parenteral delivery device and methods of use | |
| 工藤昌尚 et al. | Effects of combined treatment with micelle-incorporated cisplatinum (NC-6004) and S-1 on human gastric cancer xenografts | |
| CN100360125C (en) | Compounding composite contg. glutamine and its use | |
| Dong et al. | The New Progress and Outlook of Oral Colon-specific Drug Delivery Systemfor Treating Cancer | |
| WO2024120520A1 (en) | Use of quinoline compound in treating small cell lung cancer | |
| CN115998747A (en) | Application of KU60019 and derivatives thereof in preparation of anti-mycobacterium tuberculosis drugs | |
| Jangde | Colonic drug delivery of new approaches | |
| Singh | Formulation and Evaluation of Colon Targeted Drug Delivery System for an Anti-Amoebic Drug | |
| Bose et al. | INTERNATIONAL RESEARCH JOURNAL OF PHARMACY | |
| US20120015903A1 (en) | PHARMACEUTICAL COMPOSITION FOR INHIBITING INCREASE OF IgA |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20131009 |