• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    [assignment] Providing a non-administration preparation with good absorption and less irritant. [Resolution] The active peptide having the medicinal effect is mixed with the powder of the sorbent resin, provided that it is dry before or after mixing the active peptide having the medicinal effect with the powder of the sorbent resin.
    公开号:KR19980032364A
    申请号:KR1019970045853
    申请日:1997-09-04
    公开日:1998-07-25
    发明作者:리에 이가라시；미쯔고 다케나가；히로시 무라마쯔；데츠오 에바다；야스오 고사까
    申请人:데츠오 에바다；다까야나기 사다오；야스오 고사까；가부시기가이샤 후지야꾸힌；
    IPC主号:
    专利说明:

    Formulations for nasal administration
    The present invention relates to a formulation for nasal administration formed by mixing a powder of an active peptide having a medicinal effect with an adsorbent resin on condition that it is dry before or after mixing. will be.
    Recently, it has been desired to develop a method of administration in which an active peptide having a medicinal effect can be self-administered and at the same time a medicinal effect can be maintained without using an injection. Therefore, in general, the peptide-based drug is bioavailability that can be expected to be oral, transdermal, rectal and sublingual administration or drug efficacy other than injection. In recognition that it would be difficult to obtain (effectiveness), attempts have been made to obtain the effect by nasal mucosal mucosa as a site of administration and by administration of a peptide-based drug in a nasal manner.
    An example is Japanese Patent Application No. 7-197919. The technique in this application is a formulation for the administration of a suspension or a powder containing a powder of an ion exchange resin or an adsorbent resin alone or in combination of two or more thereof, in which an active peptide having a waxy or medicinal effect is added thereto. In addition, the ion exchange resin and the adsorption resin are within the scope of the claims, and it has been explained that the mechanism of adsorption is that insulin is released on the mucosa by the repulsive force between ions, and it is absorbed through the mucosa.
    However, this mechanism is applicable to ion exchange resins, but the mechanism in adsorption resins without ion-activating groups has not been solved in the above-mentioned Japanese Patent Application No. 7-197919. The present invention has found the electrostatic attraction as the absorption mechanism of the adsorptive resin. As a result, the adsorption resin and the insulin powder (the active peptide having the medicinal effect and the drug having the electrostatic charge other than the peptide) are attracted by the attraction force due to static electricity, and as a result, the adsorption resin which is the carrier is the insulin (the medicinal effect). Active peptide having a drug and a drug having an electrostatic charge other than the peptide). It is necessary to be in a dry state as a condition of this adhesion. It comes into contact with the mucosal surface and loses electrostatic attraction by moisture, releasing insulin. In this case, it was found that nonpolar, nonpolar adsorbent resins (e.g., styrene divinylbenzene copolymers) are more likely to favor insulin than polar, e.g., methacrylate polymers, and eventually have better absorption. .
    In addition, another important requirement besides absorption as a non-dosing agent is that there is no irritation to the nasal mucosa. Ion-exchange resins with ion-activated groups were found to have moderate stimulation to the mucous membranes, but the adsorptive resins were less irritating, and in particular, non-polar non-polar adsorption resins had almost no mucosal stimulation. Was found. As described above, an object of the present invention is to provide an agent for nasal administration, which has a lower absorption rate and a lower irritation by discovering an electrostatic attraction as an absorption mechanism of the adsorption resin, which is not disclosed in Japanese Patent Application No. Hei 7-197919. .
    1A: Styrene divinylbenzene copolymer resin. It is a figure which shows the time course of the blood glucose level after administration of an insulin mixture.
    1B: Styrene divinyl benzene copolymer resin. It is a figure which shows the time course of the plasma insulin concentration after administration of an insulin mixture product.
    Figure 2A: polymethacrylate resin (polymethacrylate) resin. It is a figure which shows the time course of the blood glucose level after administration of an insulin mixture product.
    2B: Polymethacrylate Resin. It is a figure which shows the time course of the plasma insulin concentration after administration of an insulin mixture product.
    3: Styrene divinylbenzene copolymer resin. It is a figure which shows the time course of the blood glucose level and serum insulin concentration after administering an insulin mixture product.
    4: Polymethacrylate Resin. It is a figure which shows the time course of the blood sugar level and blood serum insulin concentrations after administration of an insulin mixture product.
    5 is a diagram showing the effect on fasting blood glucose levels of normal people.
    Fig. 6 shows the effect of suppressing post-prandial blood sugar rise in normal people.
    7 is a diagram showing the effect on fasting blood glucose levels.
    8 is a diagram showing the effect on postprandial blood glucose levels.
    9 is a diagram showing the ocular mucosa irritant classification method by the method of K and Kalandra (1962).
    In the present invention, there is no particular limitation in order to adsorb the active peptide having a weak effect on the powder carrier of the adsorptive resin, and both of them may be physically uniform and stable. However, the attraction force of the adsorption is static, so in the mixed state should be as dry as possible.
    As the pharmaceutical method,
    ① The active peptide powder having the effect of drying under the dry conditions is mixed with the powder of the dried adsorbent resin by simple stirring mixing, induction mixing, or ball mill mixing.
    ② Combine the powder of the adsorptive resin with the aqueous solution or suspension of the active peptide, which is effective, and adjust the mixed suspension to evaporate to dry powder.
    ③ In the case of ① powder mixing, organic solvents such as ethanol may be added to increase the mixing uniformity.
    When the powder formulation of the present invention is administered intranasally, there is no irritation to the administration site, there is no foreign body feeling, and there is moderate scattering property, so that when spray-administered, it becomes uniform as possible to the nasal mucosa. It needs to be distributedly attached.
    Further, considering that the thickness of the mucus layer on the nasal mucosa is 5-11 μm, it is also necessary that the particles not be too large. Therefore, the average particle diameter of the powder of the adsorptive resin used in the present invention is 100 µm-10 µm, more preferably 10-70 µm, still more preferably 20-50 µm. The adsorbent resin includes non-polar adsorbent resins based on styrene divinylbenzene, such as styrene divinylbenzene copolymers, non-polar adsorbent resins based on methacrylic esters, and vinyl pyridine. ) And polar adsorbent resins based on sulfoxide amide amino acid, and the like, and non-polar adsorbent resins such as styrene divinylbenzene copolymer are most suitable as the adsorbent resin used in the present invention.
    In the preparation of the present invention, the active peptide having an effect of adhering to the adsorption resin carrier is stably attached to the carrier when preserved as a preparation, and is easily released from the carrier after being sprayed onto the nasal mucosa, It needs to be fused and absorbed into the mucosa. Therefore, the particle diameter is preferably finer than that of the carrier, more preferably 10 µm-0.01 µm, and more preferably 1 µm-0.001 µm.
    The total weight of the single-dose intranasal administration of the preparation of the present invention is preferably as small as possible considering the irritation to the administration site, and more or less is preferable considering the loss to be sprayed at a place other than the nasal mucosa. . In addition, in consideration of the workability to fill the capsule, it is desirable that it is 15 mg or more. Thus, the weight per capsule is 15-50 mg, preferably 15-30 mg, more preferably 15-25 mg. The mixing ratio of the adsorbent resin carrier and the active peptide having a medicament is not particularly limited, and is determined by the kind of the adsorbent resin carrier powder and the active peptide having medicinal effects.
    The active peptide having a medicinal effect to be formulated in the formulation of the present invention is not particularly limited as long as it has a weak topical irritation and is capable of nasal administration. Examples include, for example, insulin, glucagon, calcitonin, gastrin, and parathyroid hormone. (parathyroid hormone), angiotensin, growth hormone, secretin, lactotropic hormone, prolactin, thyrotropic hormone, melanocyte stimulation hormone (melanocyte) stimulation hormone, thyroid stimulation hormone, thyrotropin, luteinizing hormone stimulation hormone, human menopausal gohadotrophin (HMG), vasopressin , Peptide hormones such as oxitocin, oxitocin, protirelin, corticotropin and somatropin, growth hormone stimulating factor (somato Physiologically active proteins such as stratin somatostatin, G-CSF, erythropoietin, EGF, interferon and interleukin, SOD and its derivatives, urokinase, and lysozyme Enzymes are also discussed, and the following effective dosages are discussed for each agent, for example.
    Dose of active peptide with medicinal effect: adhered to carrier powder 15 to 50 mg
    10 to 80 units of insulin
    Calcitonin 10 to 100 units
    Elkatonin 10 to 100 units
    Salmon Calcitonin 10 to 100 units
    Acetyl acetate (Gn-RH derivative) 0.1 to 1 mg
    Acetic acid proretin (LH-RH derivative) 0.1 to 1 mg
    Somatropin 4 to 60 IU
    Gulkagon 1 to 10mg
    In the present invention, the drug to be mixed into the powder of the adsorbent resin may be a drug having an electrostatic charge other than the active peptide having the drug, as well as the active peptide having the drug.
    Maintaining each formulation in the formulation of the present invention in a stable manner and depending on the type of medicament, when the absolute weight is small and accurate mixing operation is impossible, gelatin, succinate gelatin, decomposed gelatin and human serum as an extender Proteins such as albine, amino acids such as aspartic acid, sugars such as mannitol and the like may be added, and the method of mixing these stabilizers or extenders with the respective drugs is not particularly limited. In addition, the mixing ratio of the extender and each drug is not particularly limited. In addition, in the formulation of the present invention, in order to increase fluidity as a powder, a lubricant of about 0.1 to 3% by weight, specifically talc, leucine, magnesium stearate, or the like may be added.
    Examples and Experimental Examples will be shown below, but the present invention is not limited thereto.
    Example 1
    100 g of dried insulin powder (approximately 25 units per mg) and 20 g of styrene divinylbenzene copolymer resin having an average particle diameter of 30 µm dried as a powder carrier were put into an agate ball mill, followed by rotational stirring for 10 minutes under room temperature and dry conditions to be uniform. Mix. Further, 300 g of the carrier powder was mixed in the same manner for 20 minutes, and then 400 g of the carrier powder and 20 g of magnesium stearate as the lubricant were mixed in the same manner for 20 minutes to obtain the present formulation. 20 mg, equivalent to 50 units of insulin (2 mg of insulin), is filled in a No. 4 gelatin capsule, packed in PTP, and put into an alumina bag. This product is administered to humans using a Puverizer.
    Example 2
    100 g of insulin powder (about 25 units per mg) and 50 g of gelatin are uniformly mixed with 10 ml of water, followed by vacuum drying to a powder. This powder and 200 g of styrene divinylbenzene copolymer resin having an average particle diameter of 30 占 퐉 dried as a powder carrier are put in agate ball mill induction, followed by rotational stirring for 10 minutes under room temperature and dry conditions, followed by uniform mixing.
    Further, 300 g of this carrier powder was mixed in the same manner for 20 minutes, and then 350 g of this carrier powder and 20 g of magnesium stearate as the glidant were mixed in the same manner for 20 minutes to obtain the present formulation. 20 mg, equivalent to 50 units of insulin (2 mg of insulin), is filled into a No. 4 gelatin capsule, which is packaged in PTP, and placed in an alumina bag. This product is administered to humans using a perbrowser.
    Example 3
    100 g of dried insulin powder (25 units per 1 mg) and 200 g of styrene divinylbenzene copolymer resin having an average particle diameter of 30 µm dried as a powder carrier were put into a ball mill in an agate agent and uniformly rotated for 10 minutes under room temperature and dry conditions. Mix. In addition, 20g of human serum albumin and 200g of frostbite powder carrier are mixed in the same manner for 20 minutes. In addition, 480 g of in-phase powder carrier and 20 g of magnesium stearate as a lubricant are mixed in the same manner for 20 minutes to obtain the present formulation. 20 mg, equivalent to 50 units of insulin (2 mg of insulin), is filled into a No. 4 gelatin capsule, and packaged in alumina bags after PTP preparation. This product is administered to humans using a perbrowser.
    Example 4
    100 g of dried glucagon powder and 200 g of styrene divinylbenzene copolymer resin having an average particle diameter of 30 µm dried as a powder carrier were put in a ball mill mortar of agate, followed by rotational stirring for 10 minutes under room temperature and dry conditions, and mixed uniformly. Further, 300 g of this carrier powder is mixed in the same manner for 20 minutes, and then 400 g of this carrier powder and 20 g of magnesium stearate as a lubricant are mixed in the same manner for 20 minutes to obtain the present formulation. 20 mg, equivalent to 2 mg of Gulkagon of this formulation, is filled into a No. 4 gelatin light capsule and packed in an alumina bag after PTP packaging. This product is administered to humans using a perbriser.
    Example 5
    100 g of gulkagon powder and 50 g of gelatin are uniformly mixed with 100 ml of water, and then dried under vacuum to obtain a powder. The powder and 200 g of styrene divinylbenzene copolymer resin having an average particle diameter of 30 µm dried as a powder carrier are put in a ball mill mortar of agate, followed by rotational stirring for 10 minutes under room temperature and dry conditions and uniformly mixed. Further, 300 g of the carrier powder was mixed in the same manner for 20 minutes, and then 350 g of the carrier powder and 20 g of magnesium stearate as the lubricant were mixed in the same manner for 20 minutes to obtain the present formulation. 20 mg, equivalent to 2 mg of Gulkagon of this formulation, is filled into a No. 4 gelatin light capsule and packed in an alumina bag after PTP packaging. This product is administered to humans using a perbriser.
    Example 6
    100 g of dried glucagon powder and 200 g of styrene divinylbenzene copolymer resin having an average particle diameter of 30 µm dried as a powder carrier were put in a ball mill mortar of agate, followed by rotational stirring for 10 minutes under room temperature and dry conditions, and mixed uniformly. In addition, 20g of human blood serum albumin and 200g of frostbite powder carrier are mixed in the same manner for 20 minutes. In addition, 480 g of in-phase powder carrier and 20 g of magnesium stearate as a lubricant are mixed in the same manner for 20 minutes to obtain the present formulation. 20 mg, equivalent to 2 mg of Gulkagon of this formulation, is filled into a No. 4 gelatin light capsule and packed in an alumina bag after PTP packaging. This product is administered to humans using a perbriser.
    Experimental Example 1
    Nasal administration test in rabbit of the insulin preparation of this invention.
    (Preparation of sample)
    Styrene divinylbenzene copolymer resin or polymethacrylate resin powder was sieved to obtain a fraction of only 20-45 μm, sufficiently dried in a dryer, and then made into a resin carrier. Under dry conditions, 20 mg of insulin was added to agate induction, and 40 mg of the resin carrier was mixed for 10 minutes. In addition, 40 mg of the resin carrier was mixed with agate for 20 minutes under dry conditions. In addition, 100 mg of carrier resin was added and mixed with agate for 30 minutes under dry conditions, and then 5 mg of magnesium stearate was mixed with agate for appropriate time. The mixed powder product of the resin carrier insulin obtained by the above method was filled with 10 mg (about 25 U as insulin) per capsule to prepare a sample.
    (Way)
    Four rabbits were sedated by subcutaneous administration of 3 mg / kg of diazepam, and then one capsule of each drug was injected intranasally using a perbrizer (product of Teijin Co., Ltd.) adapted for rabbit nasal administration. Before administration, 15, 30, 45, 60, 90, 120, 150, 180, 240, 300, 360 minutes after administration, blood glucose levels were measured using a blood glucose meter (Gulcus M, a product of Miles Sangkyo Co., Ltd.). At the same time, blood was collected from the rabbit's ear vein in a micro test tube containing 50 µl of 3% EDTA, and centrifuged at 15,000 rpm for 10 minutes to prepare a sample for insulin measurement.
    (result)
    Styrene divinylbenzene copolymer resin. The time course of the blood glucose level after the administration of the insulin mixture is shown in FIG. 1A. The time course of the plasma insulin concentration is shown in FIG. 1B. The time course of the blood glucose level after the polymethacrylate resin and the insulin mixture is shown. At 2A, the time course of the plasma insulin concentration is shown in Fig. 2B. When styrene divinylbenzene copolymer resin and insulin mixture were administered, the mean blood glucose level before administration (103.5 ± 3, 5mg / dl) became the lowest (56.6 ± 0, 5mg / dl) after 30 minutes, which was 45.5. % Decreased. This hypoglycemic activity lasted up to 120 minutes.
    On the other hand, plasma insulin concentration peaked at 425 ± 55 μU / ml 15 minutes after administration, and then gradually decreased. On the other hand, when the polymethacrylate resin and the insulin mixed product were administered, no decrease in blood glucose levels was observed at 15 and 30 minutes after administration. Plasma insulin concentrations only showed a slight increase to 35 ± 24 μU / ml at 15 minutes post-dose.
    Experimental Example 2
    Nasal administration test (1) in normal adults of the insulin preparation of the present invention
    (Preparation of sample)
    Styrene divinylbenzene copolymer resin or polymethacrylate resin powder was sieved to obtain a fraction of only 20-45 μm, dried sufficiently with a dryer, and then a resin carrier. Under dry conditions, 40 mg of insulin was placed in agate induction, and 40 mg of the resin carrier was mixed for 10 minutes. In addition, 40 mg of the resin carrier was mixed with agate for 20 minutes under dry conditions. In addition, 100 mg of the carrier resin was mixed with agate for 30 minutes under dry conditions, and then 5 mg of magnesium stearate was mixed with agate for an appropriate time. The mixed powder product of the resin carrier insulin obtained by the above method was filled with 10 mg (50 U as insulin) per capsule to obtain a sample.
    (Way)
    Two normal adult males were fasted from the night before, and in the early morning fasting state, one capsule of each formulation was sprayed into the nasal cavity using a perbrowser (product of Teijin Co., Ltd.). A blood glucose level was measured using a blood glucose meter (Gulcoaster M, a product of Miles Sankyo Co., Ltd.) at the time of administration, 10, 20, 30, 60, and 90 minutes before administration, and blood samples were collected at the same time to measure insulin (IRI) in serum. It was set as.
    (result)
    Styrene divinylbenzene copolymer resin. The increase and decrease from the pretreatment value were calculated for each of the blood glucose level and the serum insulin concentration (IRI) after administration of the insulin mixture product, and the time course is shown in FIG. 3. It is shown in FIG. 4 after administration of the insulin mixture. Styrene divinylbenzene copolymer resin. When the insulin mixture was administered, the blood glucose level was the lowest after 30 minutes, and the mean was 15.5 mg / dl lower than the pretreatment level.
    On the other hand, serum insulin concentration (IRI) peaked at 10 minutes after administration, increased by an average of 10.6 μU / ml from pre-administration, and then gradually decreased. On the other hand, polymethacrylate resin. When the insulin mixture was administered, the blood glucose level was only slightly decreased, and the serum insulin concentration (IRI) was also slightly increased. This result was in good agreement with that of the rabbit.
    Example 3
    Nasal administration test (2) in normal person of insulin preparation of the present invention
    In order to confirm whether the insulin concentration in the preparation affects the hypoglycemic action, the same normal person under the same conditions as in Experiment 2 (containing 50 U of insulin in a 10 mg preparation. A formulation containing 50 U of insulin in the cervix (neck administration 2) and a formulation containing 50 U of insulin in the 20 mg of formulation (administration 3) were prepared and administered.
    In the results of Experiment 2, the insulin preparation of the present invention was confirmed to exhibit the maximum hypoglycemic action at 30 minutes after administration. Thus, the blood glucose level was measured 30 minutes after administration, and the blood glucose level was measured after 30 minutes without administration as a control. . The results are shown in FIGS. 5 and 7. In contrast, no changes in blood glucose levels were observed, but hypoglycemia of 15, 18 and 13 mg / dl was observed in nasal administrations 1, 2, and 3, respectively.
    Experimental Example 4
    Nasal administration test (3) in normal person of insulin preparation of this invention
    Whether or not administration of this preparation can suppress blood sugar rise after meal intake in normal persons was examined. In the same normal person, the same meal was taken under the same conditions, and immediately 1 capsule of the formulation of Experimental Example 2 was administered. Blood glucose levels were measured 1 hour after the end of the meal. Nasal administration was performed three times, and blood glucose levels when no nasal administration was administered as a control were measured twice. The results are shown in FIGS. 6 and 8. The average increase in blood glucose level without nasal administration was 94 mg / dl, whereas the mean increase in blood glucose level was 67 mg / dl, and the increase in blood glucose level was suppressed.
    Experimental Example 5
    Ocular mucosa irritation test in rabbits
    Since the carrier powder in the present invention is repeatedly administered to the nasal mucosa, it is an important requirement that there is no irritation to the nasal mucosa or little. The irritation to the mucosa of the styrene divinylbenzene copolymer resin, the polystyrene sulfonate (cationic exchange resin), and the polymethacrylate resin, which are the carrier powders used in Experimental Examples 1 to 4, was examined in the ocular mucosal irritation test using rabbits. The test method of this test was in accordance with the OECD guidelines. Eventually, three rabbits were used as a control, and a test drug was administered to the eye of the eye by conjunctival sac once, and the other eye was used as a control. 1 hour, 24 hours, 48 hours, 72 hours after administration, all eyes were visually observed by the naked eye and the slit lamp. In the observation 24 hours after the administration, washing was performed in a warm bath at about 35 ° C. According to the evaluation criteria of the eye response by the Draize method, the rating of the eye response by the administration of each test drug was calculated. The maximum value of the overall scores during each observation time was obtained for each test drug and animal, and the average value was calculated. The irritation evaluation in eight steps was performed by Kay and Calandra's eye mucosal irritant classification method (FIG. 9).
    As a result, the average value of the maximum score of the styrene divinylbenzene copolymer resin is 2.7, and the third is the `` Minimally Irritating '' in the order of the lowest irritation during the eight-step evaluation. Sodium resulfonsulfate and polymethacrylate resins had a rating of 29.0, "Moderately Irritating" (5th), 3.3, and "Minimary Irritating" (3rd), respectively. Styrene divinylbenzene copolymers have very low irritation and are likely to be repeatedly administered clinically.
    No content.
    权利要求:
    Claims (13)
    [1" claim-type="Currently amended] It is characterized in that the powder of the adsorbent resin is mixed with the active peptide having the drug, provided that before or after mixing the active peptide having the drug to the powder of the adsorbent resin is dry. Formulation for nasal administration.
    [2" claim-type="Currently amended] The preparation for nasal administration according to claim 1, wherein the adsorbent resin is a nonpolar adsorbent resin.
    [3" claim-type="Currently amended] The non-administration preparation according to claim 2, wherein the nonpolar adsorbent resin is a styrene divinyl benzene copolymer.
    [4" claim-type="Currently amended] The non-administered preparation according to claim 1, 2 or 3, wherein the average particle diameter of the powder of the adsorbent resin is 100 µm-10 µm.
    [5" claim-type="Currently amended] 2. The active peptide according to claim 1, wherein the active peptide having a medicinal effect is insulin, gulkagon, calcitonin, gastrin, parathyroid hormone, angiotensin, growth hormone, secretin, lutein stimulation hormone, cytotropic hormone, melanocyte stimulating hormone, thyroid stimulation. Hormones, luteinizing stimulating holmone, pituitary gland stimulating holmone, vasopressin, okicytosine, protyreline, peptide hormonal, growth hormone stimulating factor, G-CSF, erythropoietin, EGF Non-administrative agent, characterized in that the biologically active proteins, such as interferon and interleukin, SOD and its derivatives, urokinase and lysozyme enzymes.
    [6" claim-type="Currently amended] The non-administration preparation according to claim 1 or 5, wherein the active peptide having a medicinal effect has a particle size of 10 µm to 0.001 µm.
    [7" claim-type="Currently amended] The non-administration preparation according to claim 1, wherein the powder of the adsorbent resin dried is mixed with the powder of the active peptide having a medicinal effect dried under dry conditions, that is, before mixing.
    [8" claim-type="Currently amended] The preparation for non-administration according to claim 1, wherein the powder of the adsorbent resin is mixed with an aqueous solution or suspension of an active peptide having a medicinal effect, followed by evaporation to dry powder.
    [9" claim-type="Currently amended] The non-administration preparation according to claim 1 or 7, wherein an organic solvent is added when an active peptide powder having a medicinal effect dried under dry conditions is mixed with a powder of a dried adsorbent resin.
    [10" claim-type="Currently amended] 10. The non-administration preparation according to claim 9, wherein the organic solvent is ethanol.
    [11" claim-type="Currently amended] The non-administration preparation according to claim 1, 7, 8, or 9, wherein the drug has an electrostatic charge other than the active peptide having the medicinal effect instead of the active peptide having the medicinal effect.
    [12" claim-type="Currently amended] The non-administrative preparation according to claim 1, 7, 8, 9 or 11, wherein an extender is added.
    [13" claim-type="Currently amended] The non-administration preparation according to claim 1, 7, 8, 9, 11, or 12, wherein the lubricant is added.
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    同族专利:
    公开号 | 公开日
    SE9703133D0|1997-08-29|
    FI973244D0|
    FR2754453A1|1998-04-17|
    JP3020141B2|2000-03-15|
    AU3992697A|1998-04-09|
    ITMI972144A1|1999-03-22|
    FI973244A0|1997-08-06|
    GB9718690D0|1997-11-12|
    DE19740733A1|1998-04-09|
    GB2322077A|1998-08-19|
    CA2217409A1|1998-04-07|
    ES2126536A1|1999-03-16|
    CN1180569A|1998-05-06|
    JPH10114645A|1998-05-06|
    NO974618L|1998-04-08|
    GR970100333A|1998-06-30|
    FI973244A|1998-04-08|
    DK114797A|1998-04-08|
    SE9703133L|1998-04-08|
    NO974618D0|1997-10-06|
    US5948749A|1999-09-07|
    ES2126536B1|1999-10-01|
    IT1295047B1|1999-04-27|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-10-07|Priority to JP8-282866
    1996-10-07|Priority to JP8282866A
    1997-09-04|Application filed by 데츠오 에바다, 다까야나기 사다오, 야스오 고사까, 가부시기가이샤 후지야꾸힌
    1998-07-25|Publication of KR19980032364A
    优先权:
    申请号 | 申请日 | 专利标题
    JP8-282866|1996-10-07|
    JP8282866A|JP3020141B2|1996-10-07|1996-10-07|Formulation for nasal administration|
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