CN101422436B - Dry powder composite for suction - Google Patents
Dry powder composite for suction Download PDFInfo
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- CN101422436B CN101422436B CN2007101345362A CN200710134536A CN101422436B CN 101422436 B CN101422436 B CN 101422436B CN 2007101345362 A CN2007101345362 A CN 2007101345362A CN 200710134536 A CN200710134536 A CN 200710134536A CN 101422436 B CN101422436 B CN 101422436B
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Abstract
The invention provides a dry powder compound used for suction. The dry powder compound contains a micronized active matter, a micro-powder particle vector, a fine powder particle vector decorated by phospholipid, and a coarse powder particle vector; the dry powder compound is especially suitable for preparing a suction powder spray which is high in the activity of the active matter and only needs less active matter in a single dosage.
Description
Technical field
The present invention relates to for inhalant dry powder composite, this dry powder composite comprises: micronized active substance and micro powder granule carrier (being particulate carrier), phospholipid modified fine particle carrier (phospholipid modified fine grained solid support) and coarse powder particulate vector (being the coarse grain carrier), it is active high that this dry powder composite is particularly useful for making active substance, and single dose only needs the suction powder spray of a small amount of active substance.
Background technology
The suction powder spray means that the dry powder composite for suction of micronized medicine and excipient (or nothing) composition with capsule, vesicle or multiple dose reservoir type, adopts special powder inhaler, initiatively sucks the preparation of atomization medicine to pulmonary by the patient.
The physiological structure of lung requires the active component particle very fine, it is generally acknowledged that the active substance particle diameter that can suck should be at 0.5～10 μ m, can not enter in the bronchioles greater than the particle of this particle diameter, and littler particle is then easily breathed out with breathing.So-called herein " can suck " is meant that particle sucks with breathe air and input is goed deep into to the pulmonary branches trachea.For for sucking for the dry powder, wherein the amount of the sucked part of active component is important, and is good for sucking active substance that powder should be able to guarantee to suck so that the difference between suction and the different batches is minimum at high proportion.
Active high for active substance, single dose only needs the active substance of a small amount of active component, adds the suitable excipient particular importance that then seems.At first, active substance has higher surface free energy behind micronization, and powder is easily assembled agglomerating, adds the flowability that the bigger excipient of particle diameter can improve dry powder; Secondly, excipient also plays the effect of diluent.For having determined the character of powder body basically for sucking for the dry powder usually a high proportion of relatively excipient, mobile especially true for powder body, and good flowability is the prerequisite that high precision is measured.
Unless stated otherwise, the alleged excipient of the present invention is that confession under directions sucks in the dry powder summation of other carrier except active substance, and excipient can be formed also and can be obtained by the carrier mixing of two or more components by the carrier of one-component.Generally, the carrier granular that adds particle diameter 30～200 μ m, to improve the flowability of powder body, but the adding of greater particle size carrier has caused certain problem, the absorption that mainly is active substance micropowder and carrier surface is too strong, so that active substance can not break away from carrier when sucking, and is deposited on pars oralis pharyngis together, and the effective dose that causes entering respiratory tract reduces.For addressing the above problem, need further to add the carrier of small particle diameter, at first occupy the adsorption site of particle diameter than the larger vector surface, reach the effect that improves active substance effective site deposition properties with this.But the adding of this small particle diameter carrier can reduce the flowability of powder body again.
Good should satisfy following condition at least for sucking dry powder: (1) is encapsulated into the active substance of single dose and supplies the amount of suction dry powder even, and the variation between each batch is little; (2) active component can high suction ratio use and different batches between variation little; (3) has good Emptying Rate; (4) powder mixture height dispersibility even and each batch changes little.Dry powder composite for suction provided by the invention can satisfy above-mentioned harsh conditions.
Summary of the invention
The invention provides a kind of dry powder composite for suction, it is composed as follows: micronized active substance, particulate carrier, phospholipid modified fine grained solid support and coarse grain carrier.
In the dry powder composite for suction, the quality of the fine grained solid support that the total mass ratio of micronized active substance and particulate carrier is phospholipid modified is between 1: 1～1: 20, preferably between 1: 2～1: 10, between more preferably 1: 5～1: 8.5; The quality of the total mass ratio coarse grain carrier of micronized active substance, particulate carrier and phospholipid modified fine grained solid support is between 1: 4～1: 15, preferably between 1: 5～1: 10, more preferably between 1: 7～1: 9.
Wherein micronized active substance particle diameter between 0.5～10 μ m, preferred 1～7 μ m; Wherein the particle diameter of particulate carrier is between 0.5～10 μ m, preferred 1～7 μ m; Wherein phospholipid modified fine grained solid support is meant the surface by the equally distributed fine grained solid support of phospholipid, and particle diameter is 10～20 μ m, preferred 15～20 μ m; Wherein the content of phospholipid in fine fraction is 1%～8%, and is preferred 2%～5%, more preferably 2.35%～4%; Use therein phospholipid can be lecithin, cephalin, lipositol or phosphatidic acid and their hydrogenated products, preferably lecithin and hydrogenated products thereof, more preferably hydrolecithin and phosphatidylcholine; Wherein coarse grain carrier particle diameter is 30～200 μ m, is preferably 50～150 μ m, most preferably is 80～120 μ m.
Need to prove, in above-mentioned composition, do not define the amount of micronization active substance especially.Usually the active substance activity of inhalation is very high, in for suction dry powder, a high proportion of relatively excipient has determined the character of powder body basically, to such an extent as to the amount of active substance can not obviously help to determine the size of amount of formulation and the ratio of each several part carrier, the pharmacists only needs just can make the appropriate formulation prescription according to the ratio of the dosage of active substance and each several part carrier.
If no special instructions, the particle diameter of the following stated of the present invention all refers to volume medium D50, is with 50% the value of doing volume distributed median that dispersion method records with laser-diffractometer.
The carrier that uses among the present invention comprises carrier except that phospholipid and coarse grain carrier in particulate carrier, the fine grained solid support, and the carrier of three parts can be identical or different with regard on the chemical constituent.It can be selected for use and be fit to drug use and the harmless carrier material of physiology, can be selected from monosaccharide (as glucose, arabinose), disaccharide (as lactose, sucrose, trehalose, maltose), sugar alcohol (as mannitol, sorbitol, xylitol), dextrin, starch, aminoacid (as leucine, threonine, L-isoleucine), salt (as sodium chloride, calcium carbonate) or these excipient mixture each other.Preferred three part carriers are chemically identical and be lactose or glucose, and more preferably three part carriers are chemically identical and be lactose, and most preferably three part carriers are chemically identical and be lactose monohydrate.
Active substance of the present invention is meant arbitrarily the active substance that can use by suction, includes but not limited to:
β
2-adrenoceptor agonists, as: albuterol (salbutamol), terbutaline (terbutaline), rimiterol (rimiterol), fenoterol (fenoterol), reproterol (reproterol), bitolterol (bitolterol), salmaterol (salmeterol), formoterol (formoterol), clenbuterol (clenbuterol), procaterol (procaterol), broxaterol (broxaterol), picumeterol (picumeterol), Ka Moteluo (carmoterol), Mabuterol (mabuterol), orciprenaline (metaproterenol), milveterol, indenes Da Teluo (indacaterol), disclosed formailide derivant in WO02/76933 and US6576793, disclosed aryl aniline derivatives in WO03/42164, disclosed benzenesulfonamide derivatives in WO02/88167, disclosed formula I chemical compound among the WO00/75114, disclosed formula I chemical compound among the WO04/16601, and EP1440966, JP05025045, WO93/18007, WO99/64035, US2002/0055651, WO01/42193, WO01/83462, WO02/66422, WO02/70490, WO03/24439, WO03/42160, WO03/72539, WO03/91204, WO03/99764, WO04/16578, WO04/22547, WO04/32921, WO04/33412, WO04/37768, WO04/37773, WO04/37807, WO04/39762, WO04/39766, WO04/45618, WO04/46083, WO04/80964, EP1460064, WO04/087142, WO04/089892, EP01477167, US2004/0242622, US2004/0229904, WO04/108675, WO04/108676, WO05/033121, disclosed chemical compound among W005/040103 and the WO05/044787; The glucocorticoid agent, as: budesonide (budesonide), fluticasone (fluticasone), Mo Meitasong (mometasone), beclometasone (beclomethasone), ciclesonide (ciclesonide), triamcinolone (triamcinolone), flunisolide (flunisolide), zoticasone, flumoxonide (flumoxonide), rofleponide (rofleponide), butixocort (butixocort), prednisolone (prednisolone), prednisone (prednisone), for sprinkling Buddhist nun (tipredane), at WO02/12265, disclosed steroid ester among WO02/12266 and the WO02/88167 is at WO02/100879, WO02/00679, WO03/35668, WO03/48181, WO03/62259, WO03/64445, WO03/72592, disclosed chemical compound among WO04/39827 and the WO04/66920; The non-steroidal glucocorticoid receptor antagonists is as disclosed chemical compound among patent documentation DE10261874, WO00/00531, WO02/10143, WO03/82280, WO03/82787, WO03/86294, WO03/104195, WO03/101932, WO04/05229, WO04/18429, WO04/19935, the WO04/26248; Anticholinergic bronchodilator, as: tolterodine (tolterodine), ipratropium bromide (ipratropiumbromide), tiotropium bromide (tiotropium bromide), oxitropium bromide (oxitropium bromide), glycopyrronium bromide (glycopyrrolate), disclosed chemical compound in document EP 424021, US3714357, US5171744, WO01/04118, WO02/00652, WO02/51841, WO02/53564, WO03/00840, WO03/33495, WO03/53966, WO03/87094, WO04/018422, WO04/05285; Leukotriene B4 (LTB4) antagonist, as: the medicine of describing among BIIL-284, CP-195543, DPC-11870, LTB-4 ethanolamine, LY-293111, LY-255283, CGS-025019C, CP-195543, ONO-4057, SB-209247, SC-53228 and the US5451700; Leukotriene D (LTD4) antagonist, as: montelukast (montelukast), pranlukast (pranlukast), zafirlukast (zafirlukast), An Kemi (accolate), SR-2640, Wy-48252, ICI-198615, MK-571, LY-171883, Ro24-5913 and L-648051; The PDE4 inhibitor, as: cilomilast (cilomilast Ariflo
, GlaxoSmithKline PLC), roflumilast (Roflumilast Byk Gulden), V-11294A (Napp), BAY19-8004 (Baeyer), SCH-351591 (Schering Plough), Arofylline (Almirall Prodesfarma), PD-189659/PD-168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo) and patent documentation WO92/19594, WO93/19749, WO93/19750, WO93/19751, WO98/18796, WO99/16766, WO01/13953, WO03/104204, WO03/104205, WO03/39544, WO04/000814, WO04/000839, WO04/005258, WO04/018431, WO04/018449, WO04/018450, WO04/018451, WO04/018457, WO04/018465, WO04/019944, WO04/019945, disclosed chemical compound among WO04/045607 and the WO04/037805; Phosphatase
2AStimulant medicine, as: EP1052264, EP1241176, EP409595A2, WO94/17090, WO96/02543, WO96/02553, WO98/28319, WO99/24449, WO99/24450, WO99/24451, WO99/38877, WO99/41267, WO99/67263, WO99/67264, WO99/67265, WO99/67266, WO00/23457, WO00/77018, WO00/78774, WO01/23399, WO01/27130, WO01/27131, WO01/60835, WO01/94368, WO02/00676, WO01/22630, disclosed chemical compound in WO02/96462 and the WO03/086408; Phosphatase
2BAntagonist, as: the medicine of describing among the WO02/42298; Antihistaminic, as: cetirizine hydrochloride (cetirizinehydrochloride), acetaminophen (acetaminophen), clemastine fumarate (clemastinefumarate), promethazine (promethazine), loratadine (loratidine), Desloratadine (desloratidine), diphenhydramine (diphenhydramine), fexofenadine hydrochloride (fexofenadinehydrochloride), activastine, astemizole (astemizole), azelastine (azelastine), ebastine (ebastine), epinastine (epinastine), mizolastine (mizolastine), Te Fennading (Tefenadine), and JP2004107299, disclosed chemical compound among WO03/099807 and the WO04/026841; Antidepressants, as: desitriptilina (Nortriptyline); The medicine that has antiinflammatory and expansion bronchus dual function simultaneously comprises having β simultaneously
2The medicine of-3 adrenergic receptor agonists and muscarine antagonist dual function is such as disclosed this type of medicine among US2004/0167167, WO04/74246 and the WO04/74812.Chemokine receptors (chemokine receptors) antagonist class, comprise CCR-1, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, the antagonist of these chemokine receptors of CXCR5, especially CCR-5 antagonist, as: the antagonist SC-351125 of Schering Plough company, SCH-55700 and SCH-D, the antagonist of force field (Takeda) drugmaker, as: N-[[4-[[[6,7-dihydro-2-(4-aminomethyl phenyl)-5H-benzocyclohepta alkene-8-yl] carbonyl] amino] phenyl]-methyl]-tetrahydrochysene-N, N-dimethyl-2H-pyrans-4-ammonium salt chloride (TAK-770), US6166037 (particularly claim 18 and 19), WO00/66558 (particularly claim 8), WO00/66559 (particularly claim 9), disclosed CCR-5 antagonist among WO04/018425 and the WO04/026873; Expectorant; Mucolytic; Cyclooxygenase-2 inhibitors; Platelet aggregation factor (PAF) antagonist and asthma and chronic obstructive pulmonary disease (COPD) preventive; Arthritis (antiarrhytmic) medicine; Tranquilizer (tranquilisers); Statins (statins); Cardiac glycoside (cardiac glycosides); Hormone; Antihypertensive; Antidiabetic; Antiparasitic and anticarcinogen; Tranquilizer and analgesic; Antibiotic; Rheumatism; Antifungal agent and antihypotensive; Vaccine; , antiviral agents; , albumen, polypeptide and peptide for example peptide hormone and somatomedin; Polypeptide vaccine; Enzyme; Endorphins; , lipoprotein and participation coagulation cascade system polypeptide; Vitamin and other, for example cell surface receptor blocker, antioxidant and free radical scavenger.
If exist, some in these chemical compounds can be with for example solvate form thereof administration of hydrate or these esters or salt of pharmaceutically acceptable ester, acetal, salt, solvate.The racemic mixture of above-claimed cpd and one or more optical isomers are also included within the scope of the present invention.
But the salt that suitable physiology is accepted comprises derived from mineral acid or organic acid acid or addition salts, for example chloride, bromide, sulfate, phosphate, maleate, fumarate, citrate, tartrate, benzoate, 4-methoxybenzoic acid salt, 2-or 4-hydroxy benzoate, 4-chloro benzoate, tosilate, metilsulfate, Ascorbate, acetate, succinate, lactate, glutarate, tricarballylate, hydroxyl naphthalene-carboxylate (xinafoate) or oleate or its solvate.
The above-mentioned active medicinal matter of mentioning can be used separately, also can continue or mode administering drug combinations simultaneously.Administering drug combinations can be: β
2-adrenoceptor agonists and glucocorticoid agent, β
2-adrenoceptor agonists and anticholinergic bronchodilator, glucocorticoid agent and anticholinergic bronchodilator etc.Concrete administering drug combinations mode is as ciclesonide/formoterol, fluticasone/formoterol, fluticasone/salmaterol, albuterol/ipratropium bromide, Mo Meitasong/formoterol, ipratropium bromide/fenoterol, budesonide/formoterol, beclometasone/formoterol, budesonide/desitriptilina, fluticasone/milveterol, Mo Meitasong/indenes Da Teluo, Ka Moteluo/budesonide.
Dry powder composite for suction of the present invention can filled capsules, vesicle or is made other suitable suction powder sprays, through special-purpose doser administration, preferably it is encapsulated in the capsule, and uses for the patient by inhaler.Suggestion encapsulates 1～50mg in single dosage (as every capsules) confession sucks dry powder, and the confession of preferred package 5～25mg sucks dry powder.
The suction dry powder that supplies of the present invention can prepare as follows:
(a) the carrier mixing back micronization with active substance and Sq prepares the mixing portion that becomes micronized active substance and particulate carrier;
(b) phospholipid and carrier mass are mixed with become phospholipid modified fine grained solid support part;
(c) at last two above parts are mixed with the coarse grain carrier part, obtain of the present invention for sucking dry powder.
In above preparation method, with active substance and the common micronization of carrier, the existence of carrier can reduce the loss of medicine in micronization, and is convenient to mixing.The mixed process in the step (c) wherein, it can be order arbitrarily, mixing with the coarse grain carrier as the micro powder granule in the step (a) (comprising micropowder carrier and micronized active substance) and phospholipid modified fine grained solid support are mixed earlier again, also can be with phospholipid modified fine grained solid support and the micro powder granule (comprising micropowder carrier and micronized active substance) that adds again after the coarse grain carrier mixes in the step (a).
The suction dry powder that supplies of the present invention can also prepare as follows:
(a) with the micronized active substance of active substance micronization preparation becoming;
(b) preparation of carrier micronization becomes the particulate carrier part;
(c) phospholipid and carrier mass are mixed with become phospholipid modified fine grained solid support part;
(d) at last three above parts are mixed with the coarse grain carrier part, obtain of the present invention for sucking dry powder.
In above preparation method, the mixing of different piece can be carried out with order arbitrarily, mixes with coarse component earlier as phospholipid modified fine grained solid support, and micronized active substance and particulate carrier mixing mix two parts again; Or will add micronized active substance etc. again after the mixing of three part carriers elder generation.
In two kinds of above preparation methoies, the micronization mode can be supersonic airstream pulverizing, spray drying, high speed grinding, ball-milling method, solvent method etc., and preferred supersonic airstream is pulverized.Phospholipid modified fine grained solid support part can be made through mixing to pulverize by carrier and phospholipid, mixes crushing process and can use methods such as ball milling, spray drying, high speed grinding, preferred ball-milling method; After also phospholipid can being dissolved in organic solvent, evenly spread upon carrier surface, at last organic solvent is removed; After phospholipid can also being dissolved in organic solvent, evenly spread upon carrier surface, and then mix the pulverizing preparation with another part carrier.
Dry powder composite for suction of the present invention has made full use of the distinctive character of phospholipid, makes to reduce for sucking the dry powder free energy, and powder static electricity disappears substantially, and flowability increases greatly.Phospholipid absorbs facilitation in addition to active substance, can promote drug absorption after arriving effective site, improves the active substance bioavailability.In the preparation that in the end makes, the active substance micropowder reduces greatly with the strong absorption that is unfavorable for inhalation between coarse grain carrier, capsule or vesicle, inhalation utensil, and the ratio that active substance arrives live part obviously increases.
Adhesiveness and flowability between the dry powder composite for suction carrier of the present invention tend to balance, reach finally that medicine does not separate with carrier when making dry powder composite for suction in suction apparatus, but when suction action took place, medicine and carrier can fine the separation, significantly improve deposition ratio in the effective position.
The specific embodiment
Specify the present invention below by embodiment, but the present invention is not limited in these embodiment.
Embodiment 1:
Supplementary material title prescription (1000)
Ipratropium bromide 21mg
Lactose 19.9g
Phospholipid (polyene phosphatidylcholine) 41.9mg
Preparation method:
1) the coarse grain carrier is selected INHALAC 230 lactose that the happy company of German U.S. agent produces for use, and is used to prepare microgranule and fine grained solid support;
2) the carrier lactose equivalent of ipratropium bromide 21mg and 189mg is increased progressively behind the mix homogeneously below comminution by gas stream to the 10 μ m, make the microgranule part;
3) with in the ball grinder of packing into behind 41.9mg phospholipid and the 1741mg carrier lactose mix homogeneously, ball milling is prepared into the fine grained solid support that contains phospholipid 2.35% to particle diameter 20 μ m;
4) with 2) the disposable adding 3 of gained micropowder) in the particulate of gained, common ball milling 30 minutes;
5) with 4) the gained powder joins in the 17.9g coarse grain lactose carrier, and detection level behind the mixing is according to content fill capsule.
Embodiment 2:
Supplementary material title prescription (1000)
Formoterol fumarate 12mg
Lactose 29.7g
Phospholipid (hydrolecithin) 60mg
Preparation method:
1) coarse grain carrier lactose is selected INHALAC 230 lactose that the happy company of German U.S. agent produces for use, and is used to prepare microgranule and fine grained solid support;
2) the carrier lactose equivalent of formoterol fumarate 12mg and 288mg is increased progressively mix homogeneously after comminution by gas stream become below the 10 μ m, make the microgranule part;
3) with in the ball grinder of packing into behind phosphatidase 16 0mg and the 2940mg lactose mix homogeneously, ball milling is to particle diameter 20 μ m, and preparation becomes the fine grained solid support of phosphorous fat 2.0%;
4) with 2) the gained microgranule partly is added to 3) in the fine grained solid support of gained, mixing sieves;
5) with 4) detection level behind the coarse grain lactose carrier mix homogeneously of gained powder and 26.4g, according to content fill capsule.
Embodiment 3:
Supplementary material title prescription (1000)
Ciclesonide 160mg
Lactose 30.6g
Phospholipid (soybean lecithin) 48mg
Preparation method:
1) the screening particle diameter be the Lactose hydrate of 80-120 μ m as the coarse grain carrier, and be used to prepare microgranule and fine grained solid support;
2) the carrier lactose equivalent of ciclesonide 160mg and 480mg is increased progressively mix homogeneously after comminution by gas stream become below the 10 μ m, make the microgranule part;
3) with in the ball grinder of packing into behind phosphatidase 14 8mg and the 3152mg carrier lactose mix homogeneously, ball milling is prepared into the fine grained solid support that contains phospholipid 1.5% to particle diameter 20 μ m;
4) with 2) the disposable adding 3 of gained microgranule part) in the fine grained solid support of gained, common ball milling 30 minutes;
5) with 4) the gained powder joins in the 26.88g coarse grain lactose carrier (80-120 μ m), and detection level behind the mixing is according to content fill capsule.
Embodiment 4:
Supplementary material title prescription (1000)
Budesonide 80mg
Formoterol fumarate 4.5mg
Lactose 22.7g
Phospholipid (phosphatidylcholine) 101.4mg
Preparation method:
1) the screening particle diameter be the Lactose hydrate of 80-120 μ m as the coarse grain carrier, and be used to prepare microgranule and fine grained solid support;
2) budesonide 80mg and formoterol fumarate 4.5mg are become below the 10 μ m with comminution by gas stream after the carrier lactose equivalent of 1183mg increases progressively mix homogeneously, make the microgranule part;
3) with in the ball grinder of packing into behind phosphatidase 11 01.4mg and the 2433.6mg carrier lactose mix homogeneously, ball milling is to particle diameter 20 μ m, and preparation becomes the fine grained solid support of phosphorous fat 4%;
4) with 2) the disposable adding 3 of gained micropowder) in the fine grained solid support of gained, common ball milling 30 minutes;
5) with 4) the gained powder joins in the 19g coarse grain lactose carrier, and detection level behind the mixing is according to content fill capsule.
Embodiment 5:
Supplementary material title prescription (1000)
Fluticasone 250mg
Salmaterol 50mg
Threonine 19.6g
Phospholipid (soybean lecithin) 100mg
Preparation method:
1) the screening particle diameter be the threonine of 80-120 μ m as the coarse grain carrier, and be used to prepare microgranule and fine grained solid support;
2) with fluticasone 250mg with below salmaterol 50mg comminution by gas stream becomes 10 μ m, make the micronization active substance;
3) 1700mg threonine comminution by gas stream is become below the 10 μ m, make particulate carrier;
4) with in the ball grinder of packing into behind 100mg phospholipid and the 1900mg threonine mix homogeneously, ball milling is to particle diameter 20 μ m, and preparation becomes the fine grained solid support of phosphorous fat 5.0%;
5) get 3) gained particulate carrier and 4) in the coarse grain carrier of the disposable 16g of being added to of gained fine grained solid support, mixing sieves;
6) with 2) the micronization active substance of gained, join 5) in the gained carrier, according to content fill capsule.
Embodiment 6:
Supplementary material title prescription (1000)
Albuterol 90mg
Ipratropium bromide 18mg
Mannitol 25.6g
Phospholipid (Ovum Gallus domesticus Flavus lecithin) 110.4mg
Preparation method
1) the screening particle diameter be the mannitol of 80-120 μ m as the coarse grain carrier, and be used to prepare microgranule and fine grained solid support;
2) comminution by gas stream behind the mannitol mix homogeneously of albuterol 90mg and ipratropium bromide 18mg raw material and 122mg is become below the 10 μ m, make the microgranule part;
3) with in the ball grinder of packing into behind 110.4mg phospholipid and the 1269.6mg mannitol mix homogeneously, ball milling is to particle diameter 20 μ m, and preparation becomes the fine grained solid support of phosphorous fat 8%;
4) with 3) the gained fine grained solid support adds in the 24.15g coarse grain carrier common ball milling 30 minutes;
5) with 2) the gained microgranule partly joins 4) in the gained carrier, detection level behind the mixing is according to content fill capsule.
Embodiment 7:
Supplementary material title prescription (1000)
Fenoterol 50mg
Ipratropium bromide 20mg
Lactose 29.9g
Leucine 60mg
Phospholipid (soybean lecithin) 26mg
Preparation method
1) the screening particle diameter be the lactose of 80-120 μ m as the coarse grain carrier, and be used to prepare fine grained solid support;
2) with fenoterol 50mg with below ipratropium bromide 20mg comminution by gas stream becomes 10 μ m, make the micronization active substance;
3) 60mg leucine comminution by gas stream is become below the 10 μ m, make particulate carrier;
4) with in the ball grinder of packing into behind 26mg phospholipid and the 2574mg lactose mix homogeneously, ball milling is to particle diameter 20 μ m, and preparation becomes the fine grained solid support of phosphorous fat 1.0%;
5) with 2) gained micronization active substance adds 3) in the particulate carrier of gained, mixing sieves;
6) 4 gained fine grained solid supports are mixed with the 27.3g lactose;
7) with 5) gained powder and 6 gained powder mixes, detection level behind the mixing is according to content fill capsule.
Embodiment 8: deposition ratio in the effective position:
The formoterol fumarate of different content of phospholipid sucks the deposition ratio in the effective position contrast of powder spray in the particulate.
Prescription and preparation method based on embodiment 2, keep micronized formoterol fumarate, particulate carrier part, fine grained solid support part, coarse grain carrier part to account for the constant rate of total composition, the ratio of phospholipid and lactose in the adjusting particulate, the different formoterol fumarate dry powder composite for suction of content of phospholipid in the preparation particulate.With reference to two appendix XH of Chinese Pharmacopoeia version in 2000 effective fraction medicine quantitative determination method, use and suck (the artificial larynx of powder spray active drug quantitative determination instrument, Pharmaceutical National Engineering Research Center), measure the drug effective region drug deposition amount of different dry powder composite for suction respectively, and with high performance liquid chromatograph (Waters2695), measure formoterol fumarate content with reference to high-efficient liquid phase technique (two appendix VD of Chinese Pharmacopoeia version in 2000), calculate deposition ratio in the effective position.The result shows that in content of phospholipid scope of the present invention, the drug effective region deposition significantly improves.The result is as follows:
| Content of phospholipid in the particulate (%) | 0 | 0.7 | 1.5 | 2.35 | 3.3 | 4.2 | 8.5 |
| Deposition ratio in the effective position (%) | 14.3 | 17.9 | 22.5 | 27.2 | 25.1 | 25.0 | 18.8 |
Embodiment 9: stability test:
Ciclesonide is sucked powder spray sample (pressing embodiment 3 preparations) press commercially available back (adopt the hard sheet packing of aluminium foil and PVC, and adopt damp-prrof packing), 25 ℃ ± 2 ℃ of temperature, placement for a long time keeps sample under the condition of relative humidity 60% ± 10%.After placement the 3rd, 6, the JIUYUE detection of taking a sample respectively, and compare with the initial detecting result.Ciclesonide suction powder spray sample keeps sample for a long time, and the result is as follows in investigation:
| Project | 0 month | March | June | JIUYUE |
| The content character | White powder | White powder | White powder | White powder |
| Emptying Rate | 97.1 | 96.0 | 96.2 | 95.5 |
| Total impurities | 0.38 | 0.42 | 0.46 | 0.66 |
| Content | 99.83 | 99.57 | 99.13 | 99.60 |
Claims (12)
1. dry powder composite for suction, form by micronized active substance, particulate carrier, phospholipid modified fine grained solid support and coarse grain carrier, wherein, the gross mass of micronized active substance and particulate carrier: the quality of phospholipid modified fine grained solid support is between 1: 1～1: 20; The gross mass of micronized active substance and particulate carrier and phospholipid modified fine grained solid support: the quality of coarse grain carrier is between 1: 4～1: 15; Wherein micronized active substance particle diameter is between 0.5～10 μ m; Wherein the particle diameter of particulate carrier is between 0.5～10 μ m; Wherein phospholipid modified fine grained solid support, particle diameter are 10～20 μ m, and wherein the content of phospholipid in fine fraction is 1%～8%; Wherein coarse grain carrier particle diameter is 30～200 μ m.
2. the described dry powder composite for suction of claim 1, it is characterized in that: the gross mass of micronized active substance and particulate carrier: the quality of phospholipid modified fine grained solid support is between 1: 2～1: 10.
3. the described dry powder composite for suction of claim 2, it is characterized in that: the gross mass of micronized active substance and particulate carrier: the quality of phospholipid modified fine grained solid support is between 1: 5～1: 8.5.
4. the described dry powder composite for suction of claim 1 is characterized in that: the gross mass of micronized active substance and particulate carrier and phospholipid modified fine grained solid support: the quality of coarse grain carrier is between 1: 5～1: 10.
5. the described dry powder composite for suction of claim 4 is characterized in that: the gross mass of micronized active substance and particulate carrier and phospholipid modified fine grained solid support: the quality of coarse grain carrier is between 1: 7～1: 9.
6. each described dry powder composite for suction of claim 1-5, it is characterized in that: wherein the content of phospholipid in fine fraction is 2%～5%.
7. the described dry powder composite for suction of claim 6, it is characterized in that: wherein the content of phospholipid in fine fraction is 2.35%～4%.
8. each described dry powder composite for suction of claim 1-5, it is characterized in that: wherein micronized active substance particle diameter is 1～7 μ m.
9. each described dry powder composite for suction of claim 1-5, it is characterized in that: wherein the particle diameter of particulate carrier is 1～7 μ m.
10. each described dry powder composite for suction of claim 1-5, it is characterized in that: wherein phospholipid modified fine grained solid support particle diameter is 15～20 μ m.
11. each described dry powder composite for suction of claim 1-5 is characterized in that: wherein coarse grain carrier particle diameter is 50～150 μ m.
12. the described dry powder composite for suction of claim 11 is characterized in that: wherein coarse grain carrier particle diameter is 80～120 μ m.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2007101345362A CN101422436B (en) | 2007-10-31 | 2007-10-31 | Dry powder composite for suction |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101345362A CN101422436B (en) | 2007-10-31 | 2007-10-31 | Dry powder composite for suction |
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| CN101422436B true CN101422436B (en) | 2010-12-01 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5087182B1 (en) * | 2012-06-13 | 2012-11-28 | クリニプロ株式会社 | Method for producing inhalable powder |
| JP6116206B2 (en) * | 2012-11-26 | 2017-04-19 | クリニプロ株式会社 | Method for producing inhalable powder |
| JP6033055B2 (en) * | 2012-11-26 | 2016-11-30 | クリニプロ株式会社 | Method for producing inhalable powder |
| JP5937498B2 (en) * | 2012-11-26 | 2016-06-22 | クリニプロ株式会社 | Method for producing inhalable powder |
| JP6091862B2 (en) * | 2012-11-26 | 2017-03-08 | クリニプロ株式会社 | Method for producing inhalable powder |
| GB201321712D0 (en) * | 2013-12-09 | 2014-01-22 | Pharmachemie Bv | Dry Powder Inhaler |
| CN115400103B (en) * | 2022-09-22 | 2023-11-24 | 苏州易合医药有限公司 | Porous respiratory particle and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439360A (en) * | 2003-03-07 | 2003-09-03 | 南昌弘益科技有限公司 | Dry powder composition for improvement of effective position medical deposit |
| CN1694712A (en) * | 2002-08-21 | 2005-11-09 | 诺顿·希尔思凯尔有限公司 | Inhalation composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1694712A (en) * | 2002-08-21 | 2005-11-09 | 诺顿·希尔思凯尔有限公司 | Inhalation composition |
| CN1439360A (en) * | 2003-03-07 | 2003-09-03 | 南昌弘益科技有限公司 | Dry powder composition for improvement of effective position medical deposit |
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