JP2011147541A - Lyophilized formulation held in tube - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a lyophilized formulation suitable for accurately administering a small amount of active component by a fixed quantity, and capable of being intraorally or orally administered to be consumed in one dose; and to provide a formulation method. <P>SOLUTION: An aqueous solution including a medicative component and water-soluble polymer is injected into a tube, and after freezing the tube, the tube is cut at a prescribed length to be lyophilized. Further, the tube holding the lyophilized composition is attached to an outlet of a sprayer when used, and a solvent is jetted from the sprayer, so that the composition inside the tube can be intraorally, orally or intranasally administered. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a freeze-dried preparation capable of intraoral, oral or intranasal administration suitable for accurately administering a certain amount of a medicinal ingredient, particularly a trace amount of an active ingredient, and a method for producing the same.

  2. Description of the Related Art Conventionally, a doser and a dosage form that can accurately administer a certain amount of a physiologically active substance that exerts a large pharmacological effect such as a hormone, protein, or peptide and that is disposable for each administration are conventionally known. For example, Patent Document 1 discloses a preparation administration device containing a freeze-dried preparation as an administration form capable of accurately administering a fixed amount of a solid preparation dissolved in use in the nasal cavity or on the ocular mucosa. Yes.

Patent Document 2 discloses a tablet-shaped solid preparation for oral or oral administration obtained by dispensing a mixed liquid containing a protein physiologically active substance, collagen and a water-soluble additive into a PTP molded sheet and freeze-drying it. It is shown.
All of these preparations are freeze-dried preparations, and it seems that there is no problem in content uniformity, but in order to freeze-dry, it is necessary to fill a small amount of drug solution into each drug container, and industrial mass production It is a manufacturing form that is not suitable for.

  Patent Document 3 describes that collagen and gelatin are particularly preferable as carrier components of sustained-release preparations, but lyophilization is only described as one of the concentration methods.

Japanese Patent Laid-Open No. 3-90157 International Publication No. 92/17209 Pamphlet Japanese Patent Laid-Open No. 3-163032

The solid preparation described in Patent Document 2 by the same applicant as the present application relates to an oral trace interferon preparation for oral administration. It is a porous solid preparation that is obtained by dispensing a mixed solution containing an extremely small amount of interferon, collagen and a water-soluble additive into a PTP molded sheet and freeze-dried. Although it is excellent in content uniformity, it is necessary to dispense one by one, freeze it, freeze-dry, etc. The cost was high and it was not always satisfactory.
Accordingly, the present invention provides a freeze-dried preparation suitable for accurately administering a certain amount of a medicinal component, particularly a trace amount of an active ingredient such as interferon, and capable of being used orally or orally that can be used up once. Its purpose is to provide its manufacturing method.

  In order to solve the above-mentioned problems, the present inventors have conducted intensive research and injected a medicinal ingredient and an aqueous solution of a water-soluble polymer into a tube, and after freezing, cut into a predetermined length and freeze-dried. Furthermore, the present inventors have found that the object can be achieved by combining the freeze-dried preparation with a solvent container for spraying (spray administration device), for example, a commercially available pump-type liquid discharge container at the time of use, and the present invention has been achieved. .

That is, the present invention relates to the following.
[Item 1] A freeze-dried preparation comprising a medicinal ingredient and a water-soluble polymer, which is held in a tube that can be administered orally, orally, or intranasally.

[Item 2] An oral solution, oral administration or intranasal administration obtained by injecting an aqueous solution of a medicinal ingredient and a water-soluble polymer into a tube, freezing, cutting to a predetermined length and freeze-drying A freeze-dried preparation characterized by being held in a possible tube.

[Item 3] The freeze-dried preparation according to Item 1 or 2, wherein the tube is a cartridge tube for mounting a spray dispenser.

[Item 4] A cartridge tube formulation for a spray administration device, which can be administered orally, orally or intranasally, in which a lyophilized composition containing a medicinal component and a water-soluble polymer is retained.

[Item 5] A tube containing a lyophilized composition containing a medicinal component and a water-soluble polymer, and a spray administration device capable of oral administration, oral administration, or intranasal administration, and the tube comprising the spray administration device A kit which is mounted on the spraying nozzle and sprays a solvent from a spray dispenser to enable oral administration, oral administration or intranasal administration of the composition in the tube.

[Item 6] The water-soluble polymer is collagen and / or gelatin, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, methylcellulose, gellan gum, xanthan gum, tamarind gum, carboxyvinyl polymer, polypeptide, Freezing according to Items 1 to 5, which is at least one selected from the group consisting of dextrin, cyclodextrin, pullulan, gum arabic, carrageenan, guar gum, agar, highly polymerized polyethylene glycol and methoxyethylene maleic anhydride copolymer. Dry formulations, cartridge tube formulations, and kits.

[Item 7] The water-soluble polymer is selected from the group consisting of collagen and / or gelatin, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gellan gum, xanthan gum, tamarind gum, carboxyvinyl polymer and dextrin. Item 6. The freeze-dried preparation, the cartridge tube preparation, and the kit according to Item 1-5, wherein the preparation is at least one or more selected from the above.

[Item 8] The freeze-dried preparation, cartridge tube preparation, and kit according to Item 1-7, wherein the medicinal component is a physiologically active substance.

[Item 9] The freeze-dried preparation, cartridge tube preparation, and kit according to Item 8, wherein the physiologically active substance is a cytokine.

[Item 10] The freeze-dried preparation, cartridge tube preparation, and kit according to item 9, wherein the cytokine is interferon.

[Item 11] The freeze-dried preparation, cartridge tube preparation, and kit according to any one of Items 1 to 10, further comprising polysorbate 80 in the freeze-dried preparation or freeze-dried composition.

[Item 12] The lyophilization according to any one of Items 1 to 11 above, wherein an aqueous solution containing a medicinal component and a water-soluble polymer is poured into a tube, frozen, cut into a predetermined length and freeze-dried. Preparation method of preparation, cartridge tube preparation and kit.

[Item 13] The lyophilized preparation or cartridge tube preparation described in any one of Items 1 to 4 or 6 to 11 is attached to an injection port of a spray administration device, and a drug is injected into the animal by injecting a solvent from the spray administration device. A method of oral administration, oral administration or intranasal administration.

  The subject of administration of the present invention is a general animal including a human. In particular, the present invention is an effective administration method for animals other than humans that are difficult to administer orally. Examples of animals other than humans include livestock animals and pets, such as cattle, horses, pigs, chickens, and dogs. And cats.

INDUSTRIAL APPLICABILITY The present invention is suitable for accurately administering a certain amount of a medicinal component, particularly a trace active ingredient such as interferon, and can be made disposable after each administration. It is possible to accurately administer an appropriate amount by cutting the tube in accordance with the above.
Moreover, when manufacturing this tube, since it can manufacture without the complicated operation of dispensing a chemical | medical solution to the individual container like the past, and freezing and freeze-drying, mass production becomes possible.

The freeze-dried preparation in the present invention means a tube freeze-dried preparation in which a freeze-dried composition is held in a tube, and the freeze-dried composition here contains a medicinal ingredient and a water-soluble polymer, and further pharmaceutically. Obtained by lyophilization of an aqueous solution that may contain acceptable excipients, stabilizers, sweeteners, pH adjusters, and the like, and additives for preventing adsorption to the inner wall of the tube, such as polysorbate 80 Contemplates a composition.
In the present invention, the type of medicinal component is not particularly limited as long as it is a drug that can be administered orally, orally or intranasally, and can be lyophilized. The present invention is particularly useful when a trace amount of a highly active and heat labile drug, for example, a physiologically active substance such as prostaglandin, prostacyclin, vitamin, steroid, protein or peptide is used as a medicinal ingredient. Specific examples of the protein or peptide include cytokines such as interferon, colony-stimulating factor, growth hormone, growth hormone releasing factor, insulin-like growth factor, plasminogen activator, erythropoietin, and interleukin. Examples of interferon include interferon-α, interferon-β, and interferon-γ. The amount of the medicinal component in the freeze-dried preparation of the present invention is not particularly limited as long as it can be freeze-dried, and it is preferable that a single dose is held in one tube. As a preparation that retains an amount such as one half or one third of a single dose, it may be administered twice or three times at a time. Further, based on the amount of the medicinal component per unit length, the tube may be cut and used so that the amount of medicinal component necessary for use is obtained.
For example, when the medicinal component is interferon, interferon is contained in an amount of 10 to 1000 IU, preferably 20 to 200 IU as a single dose per tube.

The water-soluble polymer used in the present invention is preferably collagen and / or gelatin, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, methylcellulose, gellan gum, xanthan gum, tamarind gum, carboxyvinyl polymer. A water-soluble polymer selected from the group consisting of polypeptide, dextrin, cyclodextrin, pullulan, gum arabic, carrageenan, guar gum, agar, highly polymerized polyethylene glycol and methoxyethylene maleic anhydride copolymer,
More preferably, it is water-soluble selected from the group consisting of collagen and / or gelatin, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, methylcellulose, gellan gum, xanthan gum, tamarind gum, carboxyvinyl polymer and dextrin. A polymer,
More preferably, it is a water-soluble polymer selected from the group consisting of collagen and / or gelatin, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gellan gum, xanthan gum, tamarind gum, carboxyvinyl polymer and dextrin. Yes,
Particularly preferred is a water-soluble polymer selected from the group consisting of collagen and / or gelatin, sodium carboxymethylcellulose, hydroxypropylcellulose, gellan gum, carboxyvinyl polymer and dextrin. These water-soluble polymers may be used alone or in combination of two or more.
The amount of the water-soluble polymer in the freeze-dried preparation is 0.1% by weight or more, preferably 0.5% by weight or more from the viewpoint of maintaining the cake shape in the tube. Is 10% by weight or less, preferably 5% by weight or less.

  The spray administration device used in the present invention is not limited as long as it can spray a certain amount of solvent from the injection port. For example, a container used in a normal mouthwash, etc. Air is sent into the device, and the internal pressure increases, so the solvent sucked in from the nozzle in the container is sprayed from the injection port. The container is used for shampoo, rinse, etc. A pump-type bottle that can be discharged is included.

  The tube used in the present invention may be a tubular or cylindrical tube that can be attached to the spray port of the spray administration device. For example, the outer diameter of the tube is 2 to 6 mm, preferably 2 to 4 mm, more preferably about The inner diameter of the tube is 1.5 to 5.5 mm, preferably 1.5 mm to 3.5 mm, more preferably about 2 mm. Moreover, the length of a tube is 10-70 mm, for example, Preferably it is 20-50 mm, More preferably, it is about 30 mm. Moreover, about the length of a tube, you may prepare longer than these illustrated length, and you may cut | disconnect and use a tube so that it may become the quantity of a medicinal component of a quantity required at the time of use. Examples of the material of the tube include polyethylene, polypropylene, polystyrene, fluororesin [Teflon such as tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (PFA)] and the like. The cartridge tube for mounting a spray dispenser is a detachable tube that can be mounted on the spray dispenser, and has the same shape, material, etc. as the above tube.

  The spraying method according to the present invention is not limited to the above-mentioned spray administration device, and may be a device that can extrude a solvent such as a syringe at once.

  The solvent sprayed from the spray administration device used in the present invention is a solvent used in ordinary oral solutions, and is not particularly limited as long as it can dissolve the freeze-dried composition of the present application at the time of spraying. Examples include aqueous solutions such as saline, acidic or alkaline aqueous solutions, and ethanol water.

  In the method of oral administration, oral administration or intranasal administration in the present invention, a tube holding the freeze-dried composition of the present application is attached to the tip of the spray port of the spray administration device, and the other tube not attached is attached. A method in which the lyophilized composition in the tube is dissolved in the spray solvent by inserting the tip into the patient's mouth or nose and spraying the spray solvent, and the drug solution dissolved in the oral cavity, oral cavity or nasal cavity is administered It is.

Next, a method for producing a freeze-dried preparation retained in the tube of the present invention will be described in detail.
The preparation method of the present invention is characterized in that an aqueous solution of a medicinal ingredient and a water-soluble polymer is injected into a tube, frozen, cut into a predetermined length and freeze-dried. It is particularly useful for obtaining a preparation that is suitable for filling medicinal ingredients and is excellent in content uniformity.
That is, a viscous aqueous solution of a water-soluble polymer is prepared, and a medicinal component is added to this and stirred. At this time, pharmaceutically acceptable excipients, stabilizers, sweeteners, pH adjusters and the like and additives for preventing adsorption to the inner wall of the tube, such as polysorbate 80, can be added as necessary.
Dispense this mixture into a disposable syringe and centrifuge defoam as necessary. Centrifugation at the time of centrifugal defoaming is performed under conditions of about 2000 to 3000 rpm for about 5 to 10 minutes, for example. The product thus obtained is extruded into a tube and frozen. Although the length of the tube to inject | pour is arbitrary, since press will become high when it lengthens too much, 300-1200 mm is preferable as length of a tube. Moreover, dry ice, liquid nitrogen, a freezer, etc. can be utilized as a freezing method.
After freezing, the frozen tube is cut into a predetermined length with a cutter, placed in a tray, and freeze-dried by a conventional method to obtain a freeze-dried preparation retained in the tube.
The obtained preparation is preferably packed in an aluminum bag together with a desiccant such as silica gel in order to keep the activity and quality stable.
The preparation of the present invention is not only applicable to humans, but it is possible to accurately administer a certain amount of a medicinal component, particularly a trace amount of active ingredient, to cattle, horses, pigs, chickens and other small animals such as dogs and cats.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
Example 1
A solution was prepared by the following procedure so that the formulation shown in Table 1 was obtained. Carboxyvinyl polymer and sucrose were added to purified water and dissolved by stirring. Next, pH was adjusted using sodium hydroxide or hydrochloric acid. After adjusting the pH, polysorbate 80 and interferon-α were added and stirred, and the total amount was adjusted with purified water.
The prepared solution was dispensed into a 20 mL disposable syringe, centrifuged and degassed (2500 rpm, 5 minutes), and filled into a PFA tube having an outer diameter of 3 mm, an inner diameter of 2 mm, and a length of 330 mm. The filled PFA tube was frozen in a freezer. After freezing, the frozen tube was cut into a length of 30 mm using a cutter. The cut tube was placed in a tray and freeze-dried to obtain a tube freeze-dried preparation.

Example 2
A solution was prepared by the following procedure so that the formulation shown in Table 2 was obtained. Atelocollagen, gelatin and sucrose were added to purified water and dissolved by stirring. Next, after confirming the pH, polysorbate 80 and interferon-α were added and stirred, and the total amount was adjusted using purified water.
The prepared solution was dispensed into a 20 mL disposable syringe, centrifuged and defoamed (2000 rpm, 5 minutes), and filled into a PFA tube having an outer diameter of 3 mm, an inner diameter of 2 mm, and a length of 330 mm. The filled PFA tube was frozen in a freezer. After freezing, the frozen tube was cut into a length of 30 mm using a cutter. The cut tube was placed in a tray and freeze-dried to obtain a tube freeze-dried preparation.

Examples 3-8
The excipients in Table 1 were replaced with the water-soluble polymers shown in Table 3, and Examples 3 to 8 were obtained in the same manner as in Example 1.

Examples 9-10
Examples 9 to 10 were obtained in the same manner as in Example 1 or 2 using the components shown in Table 4.

Examples 11-13
Examples 11 to 13 were obtained in the same manner as in Example 1 using the components shown in Table 5.

Reference Examples 1-5
Using the water-soluble polymer shown in Table 6, an aqueous solution was prepared such that the blending amount in 100 g was the ratio shown in Table 6. The pH of the solution was adjusted using hydrochloric acid or sodium hydroxide so as to be in the range of pH 6-7. The prepared solution was processed in the same manner as in Example 1 to obtain Reference Examples 1 to 5.

Test example 1
The tube freeze-dried preparation obtained in Example 1 and Example 2 was put together with 1 g of silica gel in a plastic bottle, tightly sealed and placed in an aluminum bag, and then stored at 40 ° C./75% RH for 2 weeks and 1 month for stable Sex was evaluated. Table 7 shows the results of measuring the interferon-α content of the tube freeze-dried preparation by the ELISA (Enzyme Linked Immunosorbent Assay) method. From Table 7, it can be seen that the tube freeze-dried preparations of Examples 1 and 2 are stable after long-term storage.

Test example 2
Table 8 shows the observation results of the appearance (cake shape) immediately after freeze-drying of the freeze-dried preparations of Examples 1 to 13 and Reference Examples 1 to 5, and the evaluation results of the drug dischargeability in the tube by the administration device. As the administration device, a commercially available 150 mL dispensing bottle (pump type) was used. The solvent is purified water, and the discharge liquid amount is 1 mL. Moreover, as a hygroscopic test, the observation result of the external appearance (cake shape) after storing the freeze-dried preparation in an environment of room temperature / 75% RH for 1 hour is shown. From Table 8, it can be seen that Example 1 using carboxyvinyl polymer alone has hygroscopicity, but Reference Examples 1 to 5 combined with other water-soluble polymers have improved hygroscopicity.

Test example 3
For the tube freeze-dried preparations obtained in Example 1 and Example 9, Example 2 and Example 10, the interferon titer recovery rate with respect to the charged titer per tube was examined. Table 9 shows the results of measuring the interferon titer recovery rate of the tube freeze-dried preparation by the ELISA (Enzyme Linked Immunosorbent Assay) method. From Table 9, it can be seen that by adding polysorbate 80, the interferon titer recovery rate is increased.

Claims (16)

  A freeze-dried preparation comprising a medicinal ingredient and a water-soluble polymer, which is held in a tube that can be administered orally, orally or intranasally.   The freeze-dried preparation according to claim 1, obtained by injecting an aqueous solution of a medicinal ingredient and a water-soluble polymer into a tube, freezing, cutting to a predetermined length and freeze-drying.   The freeze-dried preparation according to claim 1 or 2, wherein the tube is a cartridge tube for mounting a spray dispenser.   Water-soluble polymer is collagen and / or gelatin, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, methylcellulose, gellan gum, xanthan gum, tamarind gum, carboxyvinyl polymer, polypeptide, dextrin, cyclodextrin The freezing according to any one of claims 1 to 3, which is at least one selected from the group consisting of pullulan, gum arabic, carrageenan, guar gum, agar, highly polymerized polyethylene glycol and methoxyethylene maleic anhydride copolymer. Dry formulation.   The water-soluble polymer is at least one selected from the group consisting of collagen and / or gelatin, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gellan gum, xanthan gum, tamarind gum, carboxyvinyl polymer and dextrin The lyophilized preparation according to any one of claims 1 to 3, which is as described above.   The lyophilized preparation according to any one of claims 1 to 5, wherein the medicinal component is a physiologically active substance.   The lyophilized preparation according to claim 6, wherein the physiologically active substance is a cytokine.   The lyophilized preparation according to claim 7, wherein the cytokine is interferon.   The lyophilized preparation according to any one of claims 1 to 8, further comprising polysorbate 80.   A tube containing a lyophilized composition containing a medicinal component and a water-soluble polymer, and a spray administration device capable of oral administration, oral administration, or intranasal administration, and the tube as an injection port of the spray administration device A kit that is mounted and sprayed with a solvent from a spray administration device to enable oral administration, oral administration, or intranasal administration of the composition in the tube.   Water-soluble polymer is collagen and / or gelatin, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, methylcellulose, gellan gum, xanthan gum, tamarind gum, carboxyvinyl polymer, polypeptide, dextrin, cyclodextrin The kit according to claim 10, wherein the kit is at least one selected from the group consisting of pullulan, gum arabic, carrageenan, guar gum, agar, highly polymerized polyethylene glycol and methoxyethylene maleic anhydride copolymer.   The water-soluble polymer is at least one selected from the group consisting of collagen and / or gelatin, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gellan gum, xanthan gum, tamarind gum, carboxyvinyl polymer and dextrin The kit according to claim 10, which is the above.   The kit according to any one of claims 10 to 12, wherein the medicinal component is interferon.   The kit according to any one of claims 10 to 13, further comprising polysorbate 80 in the lyophilized composition.   The lyophilized preparation according to any one of claims 1 to 9, wherein an aqueous solution containing a medicinal component and a water-soluble polymer is poured into a tube, frozen, cut into a predetermined length, and lyophilized. Manufacturing method.   The lyophilized preparation according to any one of claims 1 to 9 is attached to a spray port of a spray administration device, and a solvent is sprayed from the spray administration device, whereby the drug is administered to the animal orally, orally, or intranasally. How to administer.