JP2012051913A - Method for producing elongated drug formation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an elongated drug formation for parenteral drug administration.SOLUTION: There are provided a method and a system for producing an elongated drug formulation suitable for being injected through the skin of a patient without using a needle or a cannula. The drug formulation is produced by compressing a drug granulate in a cavity of a system comprising a roller and a surface, wherein the roller roles over the surface to compress the granulate into the formulation.

Description

  The present invention relates to a method and apparatus for producing an elongated dosage form of a drug, and more particularly to an elongated dosage form having sufficient strength to be injected through a patient's skin without the use of a needle or cannula.

  Some drugs are administered parenterally because a rapid effect of the drug is desired or because the nature of the drug causes the drug to break down in the stomach before any effect occurs.

  The most widely used method for parenteral injection of drugs is by injection of an aqueous solution using a hypodermic syringe. There are many inherent problems associated with the use of aqueous solutions. To inject a certain amount of drug, a much larger amount of water and various additives must also be injected, resulting in a large volume injection. Especially in intramuscular injections, the pain associated with injections is not caused by skin puncture, but mainly by such volume injections. Some reduction in volume will lead to a reduction in patient pain.

  Injection of drugs as solid particles has been discussed, such as powder injection and injection of a dosage form with a needle shape, the latter being administered in a higher regime than powder.

  WO96 / 08289 (Societe de conseils de recherches et d'application scientifiques S.A) discloses a medicament having one toothpick shape at one end. Its size is from 1 mm to 3 cm in length. It is described that the medicament has a crushing strength of 8 millipoise and should be prepared using conventional techniques such as compression heat fusion or extrusion, without mentioning any technique in detail.

  Macro needles for injection are also disclosed in WO96 / 03978 (Quadrant Holdings Cambridge Ltd). These needles are 0.1 to 4 mm in diameter and 30 mm long. The needle comprises a glassy carrier and an effective amount of at least one searcher and is prepared by extrusion.

  In order to obtain a satisfactory solid parenteral injection dosage form, the injectable dosage form must have a small volume to avoid injection pain and to achieve the desired dissolution rate. The dosage form should also be given a well-defined strength to allow it to penetrate the patient's skin, whether animal or human. Furthermore, the dosage form should be stable at ambient temperatures for long periods of time, both in terms of its strength and structure, and the biological activity of the drug. The predetermined strength may be given by using a carrier in addition to the drug to be administered. The carrier used to give the required strength should be composed of compounds that are histocompatible and listed in the pharmacopoeia.

  The compression of granules consisting of the active compound and optional carrier material is known in the tablet compression art, where the granules are metered into the cavity and the plunger is subsequently introduced into the cavity. Tablets are mostly compressed into a cylindrical shape with a relatively short length compared to the diameter of the cylinder. Because tablets are often disintegrated by body fluids and enzymes in the stomach and intestine when swallowed, the strength of the tablet is not critical with respect to its function.

  In order to compress a dosage form to be injected parenterally, the metering process for filling the matrix is impaired, possibly due to the small size of the dosage form, so the usual tablet compression method is applied. I found it impossible. Furthermore, it appears that the relevant strength cannot be obtained by using conventional compression techniques.

WO96 / 08289 WO96 / 03978

  Accordingly, it is an object of the present invention to provide a method for producing an elongated dosage form for parenteral drug administration.

This is accomplished by the method of the present invention for producing an elongated dosage form, wherein the method places a first roller in close proximity to one surface and between the first roller and the surface. Forming a cavity and defining the shape of the dosage form by the cavity;
Supplying drug granules into the gap between the first roller and the surface;
Rotating the roller against the surface and thereby applying pressure to the drug granules to form the dosage form in the cavity;
Separating the first roller from the surface;
Releasing the compressed dosage form from the pocket cavity.

  As used herein, the term “elongated” is used in the usual sense, that is, the length is greater than the width or diameter of the dosage form.

  The invention further relates to an apparatus for producing an elongated dosage form, the apparatus being formed between a first roller disposed adjacent to a surface and the first roller and the surface. A drug in the cavity by rotating a cavity, means for supplying drug granules into the gap between the first roller and the surface, and rotating the roller against the surface Means for compressing the formulation, means for releasing the first roller from the surface, and means for releasing the compressed dosage form from the pocket cavity.

It is the schematic which shows the roller provided with the cavity along the surrounding surface. FIG. 2 is a schematic view showing a double roll compression device having two oppositely rotating rollers and having a cavity designed as a recess in the peripheral surface of these rollers. It is the schematic which shows the roller provided with the cavity. FIG. 3 is a schematic view from above of one of the rollers having several cavities for the elongated dosage form. FIG. 3 is a schematic top view of another roller illustrating a cavity for an elongated dosage form with a pointed end. Figure 2 is a schematic view from above of a roller with several cavities for an elongated dosage form with a pointed tip.

  The present invention relates to a method for producing an elongated dosage form, as well as an apparatus therefor.

  <Cavity> The dosage form is manufactured in a cavity formed by a first roller and one surface. The cavity defined between the first roller and the surface may be either in the roller or in the surface. In any case, the shape of the dosage form is defined by the cavity when the roller rotates on the surface. Although the term “on the surface” is used, there is no intention to limit the present invention to a roller rotating on a horizontal surface. The roller and the surface can be in any position with respect to each other. The only requirement is that the roller is adjacent to the surface and that the cavity is at least substantially closed by the roller so that pressure can be applied to the drug granules therein.

  The cavity may have any suitable shape as long as the length of the cavity is greater than the width or diameter of the cavity. Furthermore, the cavity should be such that the dosage form can be easily released after compression. The cross section of the cavity may be any suitable shape, such as a semicircular or V shape. Thereby, the dosage form will have the same cross-section after compression. The axis of the elongated cavity is preferably perpendicular to the direction of rotation of the roller to obtain the maximum pressure applied to the drug granules in the cavity.

  In one embodiment, the cavity is a pocket cavity disposed in the roller. It should be understood that the term cavity means at least one cavity, preferably several cavities, on the circumferential surface of the roller. Thus, the roller may be provided with several pocket cavities around its circumference, thereby producing several dosage forms. By rotating a roller across the surface, the drug granules are compressed between the roller and the surface by the pressure applied to the drug granules, forming a dosage form in the cavity.

  The pocket cavity may be formed as a recess in the roller. However, it is also within the scope of the present invention to individually place the pocket cavities on the protrusions on the rollers.

  In another embodiment, the surface is provided with at least one cavity, more preferably several cavities are arranged on the surface. Thereby, a metered layer of drug granules is applied onto the surface and into the cavity, and then the rollers are driven and rotated across the surface to compress the drug granules into a dosage form.

  The cavity may also be formed by a pocket cavity of the first roller and a subcavity on the surface. In that case, the dosage form is defined by the sum of the two cavities, and it is possible to obtain a more finely shaped dosage form. By using two cavities to produce a single dosage form, it is possible to design what amount of drug formulation should be defined by each cavity. In particular, the amount of dosage form defined by both the secondary cavity and the pocket cavity depends on the predetermined dosage form shape. However, it is also important for the manner in which the dosage form is released from the cavity.

  By forming a single cavity that defines the majority of the dosage form, it is possible to leave the dosage form in it after the roller is removed from the surface. In particular, if the majority is formed in rollers, for example, the dosage form can be discharged onto a conveyor belt placed away from the surface, thereby facilitating the transportation of the dosage form It is. Therefore, in one embodiment of the present invention, it is preferred that the internal shape of the pocket cavity defines a portion that is greater than half the dosage form outline.

  However, the shape of the particular dosage form to be manufactured may in some cases require that the internal shape of the secondary cavity be substantially the same as the internal shape of the pocket cavity. Thereby, it is possible to produce a substantially circular or elliptical dosage form. Thus, by using two cavities, the elongated dosage form can take the form of a rod having a substantially circular cross section.

  Another preferred shape is a rod having a substantially triangular, square or polygonal cross section.

  The mutual movement of the roller and the surface may be set appropriately in a specific device. The surface may be stationary, in which case the roller performs an axial movement parallel to the surface in addition to the rotational movement of the roller. In another embodiment, where the roller is fixed and only rotational movement of the roller is possible, the surface may move as when the surface is part of a conveyor belt. Of course, any suitable combination of these two variants is possible.

  The transport belt preferably comprises a subcavity as defined above, which is either directly contained within the transport belt, or at least two transport parts cooperate to define a subcavity. The drug granules may then be applied to the surface before a roller passes through the surface.

  <Double Roll Press> In another preferred embodiment, the surface described above is the peripheral surface or surface of the second roller, whereby the first roller and the second roller function as a double roll press. To do. Double roll presses achieve compression by sandwiching the granules between two opposing rotating rollers, at least one of which has a cavity.

  Compression pressure <Gap supply> By combining the applied pressure with a sufficient amount of granules suitable for a particular cavity, a predetermined strength of the dosage form is obtained.

The pressure applied to the drug formulation is preferably 25 to 5000 kg / cm ² , more preferably 100 to 1000 kg / cm ² , whereby a dosage form having the required strength and stability can be obtained.

  Metering the dosage form to ensure that a sufficient amount is compressed for each cavity may be done by any means appropriate for the small size cavity in question. Preferably, the drug formulation is filled into the cavity and the space above and around the cavity prior to compression. The metering itself may be done by a cut-off mechanism on the roller, or by a partition tool that divides the drug formulation into metered doses prior to compression.

  The gap between the roller and the surface is preferably continuously supplied with a drug formulation. This supply may be performed by any appropriate method. In one embodiment, the gap is fed by a feeding device with a screw feeder (with which the drug granules are pre-compressed). The screw feeder or the force feeder may be arranged like a vertical straight or slightly tapered screw feeder and an inclined straight screw feeder, a vertical and tapered screw feeder or a horizontal screw feeder. The arrangement of the screw feeder most depends on the arrangement of the rollers relative to the surface.

  In the case of a horizontal surface to be adjacent to the roller, the screw feeder may be placed almost in equilibrium with the surface that feeds the gap. When using a substantially vertical screw feeder, gravity is part of the pre-compression force applied to the drug granules. Thus, the feeding mechanism is characterized by the pressure generated by the gravity or force feed device and the friction between the material and the roller surface.

  In another embodiment, the gap is filled by simply applying a layer of drug granules to the surface before rotating the roller. Next, a stopper breakthrough mechanism that prevents movement of the drug granules may be provided.

  The gap between the roller and the surface is highly dependent on the size of the roller. The larger the gap, the more drug granules can be filled into the cavity before compression, thereby increasing the density of the compressed formulation and leading to the production of higher strength dosage forms .

  <Supply pressure> As mentioned above, pressure may be applied to the drug granules prior to supply, as by pre-compression of the granules. However, it is more preferred to apply pressure during the supply of drug granules. This pressure may be applied by a screw feeder or a pressure piston.

  In one embodiment, the drug granules are pressed against the rod prior to feeding into the gap. Thereby, the rod is divided into smaller pieces adapted to the gap between the roller and the surface by a cutting mechanism or simply by a protrusion on the roller itself. Such protrusions may be part of the cavity as described above.

  <Continuous-Stepwise Production> The method for producing the dosage form is preferably carried out as a continuous method, in which the feeding step and the compression step are carried out alternately in succession. The roller preferably rotates continuously on the surface.

  However, it is convenient to perform the steps of alternately supplying and compressing stepwise, in which case the supplying step is performed while the roller is stationary, and then the roller is rotated to perform the compressing step. .

  Whether continuous or stepwise is selected, the compressive force is preferably a predetermined rest time for each cavity, preferably 1 msec to 50 sec per cavity, more preferably 5 msec to Holds for 5 sec.

  <Drug Granule> The fluidity of the drug granule is an important feature for obtaining a predetermined dosage form. Accordingly, the drug granules are preferably granulated into a powder, where the average diameter of the granules is 10-250 μm, preferably 20-150 μm, more preferably 25-100 μm. Furthermore, for granules that are uniformly distributed in the cavity before and during compression, the ratio of the average diameter of the drug granules to the cross-sectional diameter of the dosage form is preferably 1: 2 or less, more preferably 1: 4. is there. In particular, for the production of pointed dosage forms, it is important that the granules are evenly distributed in the cavity part forming the pointed end.

  Preferably, the dosage form should be essentially free of trapped air. For the strength of the dosage form, it is very important that very little air is trapped inside the dosage form during processing in order to prevent air from being introduced into the compressed dosage form. . Apart from reducing the strength, the trapped air takes up unnecessary space and reduces the amount of active ingredient contained in the dosage form.

If too much air is trapped in the drug granules, the granules will not be compressed enough, which will reduce the strength of the dosage form. Accordingly, it is an object of the present invention to provide high density drug granules in the gap. The density of the uncompressed drug granules is preferably 0.1 to 1.6 g / cm ³ , for example 0.4 to 0.8 g / cm ³ . Increasing the density of the drug granules can be done by using a vacuum or by pre-compression of the drug granules as described above.

  By using the previously described density granules, compression results in an increase in density from the cavity granules to the dosage form, and the density of the compressed dosage form is at least twice that of the uncompressed drug granules. , Preferably at least 2.5 times, more preferably even higher.

  Drug granules are composed of the active ingredients of the drug, as well as any binders and other additives. Additives and optional binders may be granulated with the drug or they may be mixed uniformly as a powder. The advantage of this embodiment is that the active ingredients and additives can be mixed in an essentially dry state where the amphoteric component is in the form of a powder.

  <Drug dimensions> Here, when referring to the preferred dimensions of the dosage form, the dimensions of the substantially circular rod are used as a measure of the cross-sectional area. For triangular or other shaped rods, the cross-sectional area correlates with the diameter of the corresponding circular rod. The diameter of the elongated dosage form is preferably 0.2 to 1.0 mm, such as more preferably 0.3 to 0.7 mm, more preferably 0.4 to 0.6 mm. The diameter of the dosage form is important with respect to the pain associated with injection of the formulation, the smaller the diameter, the better. However, it is important that the diameter is not too small to obtain a sufficient amount of drug in the formulation to be injected. By providing a dosage form of this thickness, it was determined that it could be injected essentially without pain. A further advantage is that as the diameter decreases, only a small force is required to penetrate the skin. With the needles formed in the dosage form according to the invention, it was found that even these dimensions have the strength necessary to penetrate the skin or mucosa upon injection. A further advantage of using a smaller diameter is a higher surface area: volume ratio than with a larger diameter. Thereby, this dosage form dissolves more rapidly and drugs can be introduced into body fluids to exert their effects. However, a diameter that is too small requires a very long dosage form to contain a given amount of therapeutic agent. Also, if the diameter is too small, the compressive strength of the dosage form will be reduced and may break upon injection.

  Accordingly, the ratio of the length of the elongated dosage form to the diameter of the elongated dosage form is preferably 100: 1 to 3: 1, more preferably 100: 1 to 5: 1, and the length of the elongated dosage form. Is preferably 1 to 20 mm, more preferably 2 to 10 mm. Since long dosage forms can feel as protruding from the subcutaneous tissue into the skin, too long dosage forms increase the risk of giving the person being injected some unpleasant feeling until the dosage form is broken down Let

  In practice, the length of the dosage form is largely determined by the dose of the therapeutic agent, the amount of binder and the selected diameter. The dose of many therapeutic proteins is approximately 1 mg. 1 mg of protein, excluding the binder, roughly corresponds to a cylinder with a diameter of 0.5 mm and a length of 3 mm. If such a dosage form containing 1 mg protein is manufactured from 50% therapeutic agent and 50% binder, the dosage form has a length of 6 mm. When the required dosage is small, the size of the dosage form will decrease accordingly. In a 50% binder dosage form with a diameter of 0.5 mm, a 1/3 mg protein dose has a length of approximately 2 mm. The present invention is not limited to any particular volume, which is determined by the length of the dosage form and the lineage. In most cases, the volume of the dosage form is less than 5 μL, preferably less than 1 μL. Volumes greater than 0.25 μL can be obtained for small dose therapeutic agents. Thus, the dosage form having a diameter of 0.5 mm and a length of 2 mm has a volume of 0.39 μL.

  <Cavity Configuration> The first roller preferably includes several pocket cavities to provide an industrially applicable method. Thus, the first roller according to the present invention comprises at least two pocket cavities, preferably more than ten cavities. The number of pocket cavities depends on the distance between the cavities as well as the circumference of the roller. In order to optimize production, it is preferred that the shortest distance between the centers of two adjacent cavities corresponds to at least the diameter of the dosage form, preferably at least 1.2 times the dosage form. Thereby, any cartridge band formation is avoided. The term cartridge banding refers to the phenomenon where two dosage forms made in adjacent cavities are joined by a flat layer of compressed dosage forms. The distance between the centers of two adjacent cavities corresponds to 2-6 °, preferably approximately 4 °, of the roller circumference, whereby 90 pocket cavities are arranged in the roller.

  The dimensions of the roller are mainly adapted to the dimensions of the dosage form to be produced. The diameter of the roller is preferably at least 1 cm, more preferably at least 4 cm.

  The roller may be made of any material suitable for the above pressure. Hardened steel or ceramic is particularly suitable. The temperature of the roller, the surface and the cavity will be room temperature for most embodiments. However, it is convenient to use different temperatures of the cavities to increase compression. Thus, in one embodiment, the cavity during manufacture of the dosage form is above room temperature.

  To facilitate the dosage form release process, the cavity may be heated during compression and subsequently cooled during dosage form manufacture.

  <Point> Although the dosage form itself has a very small cross section, it has been shown that pain associated with injection of the dosage form is reduced when the dosage form has a point.

  As a human skin model, pig abdominal skin is used in injection tests. Graphite rods with various tip shapes are pressed into pig skin using Lloyd Instrument LR5K, UK. The pressure is measured in Newton as a function of distance. Compare different rod shapes using maximum force. If the rod does not have a point (180 °), satisfactory results are not obtained and the rod breaks before it is introduced into the skin. A graphite rod with a conical tip (vertical angle 90 °) penetrates the skin well. However, a 60 ° apex angle significantly improves skin penetration. The tip with an angle of less than 30 ° is very thin and fragile.

  Thus, the tip is preferably tapered at an acute angle, the angle being less than 90 °, preferably less than 75 °, more preferably less than 60 °. The tip may take any shape depending on the shape of the dosage form itself. Thus, for a substantially circular dosage form, the tip has a conical top, whereas for a dosage form with a rectangular cross-section, it has a pyramidal shaped tip. In a more preferred embodiment, the apex angle of the apex should be 30-110 °, preferably 40-90 °, more preferably 50-70 °.

  The dosage form can be formed by a cylindrical portion and a pointed portion. In this case, another way of forming the tip is to reduce the radius from the starting point of the tip, ie from the cylindrical part of the part to the narrowest part of the tip. The radius is preferably reduced by at least 30%, for example by at least 40%. Apart from this decrease in radius, it is better to round the tip.

  The tip is the most delicate part of the dosage form during compression, particularly when the dosage form is released after compression. It is very important that the tip does not break during demolding and subsequent transport and storage. In an apparatus using pocket cavities and sub-cavities in the surface, the pointed portion is preferably defined by a portion of the internal shape of the pocket cavity, with the portion exceeding the half of the pointed portion outline of the dosage form. To be molded.

  <Mold release-release> When pressure is applied to the drug granules in the cavity, the roller must be released from the surface. The roller is preferably released by continuously moving the roller relative to the surface, thereby releasing the cavity and releasing the compressed dosage form from the cavity.

  It must be ensured that the collapse of the compressed dosage form (especially its tip) does not take place during release.

  The dosage form can be released from the cavity by gravity itself, depending on the roller and surface design. However, the release is preferably controlled, for example by suction release or expulsion release.

  The destroying means is preferably a destroyer disposed in the cavity. This destroyer may be located in the middle of the cavity, i.e. in the middle of the cavity, or at one end of the cavity. In the latter case, the destroyer is preferably placed at the end with the tip of the prescription.

  Regardless of the release form, the dosage form may be conveyed directly to the packaging means when released from the cavity. This is particularly relevant when the dosage form is released by the expelling means, whereby the dosage form can be expelled into the package.

  In a further embodiment, continuous bands line each cavity, in which case the dosage form is released by removing the continuous band from the cavity after compression. In a preferred embodiment, the continuous band is part of the dosage form package. This is particularly relevant when both the cavity and subcavity are lined with continuous bands, which can form the top and bottom of the package after compression.

  <Strength> The term strength means that the dosage form has sufficient compressive strength to penetrate the patient's skin. It has been experimentally determined that a pressure of at least about 0.7 Newton is required to penetrate the human epithelium in the claimed dosage form. Less pressure is required to penetrate the mucosa. Ultimately, the dosage form must be able to withstand such pressures.

  This strength can be tested with a force gauge tester such as Advanced Force Gauge AFG-250N available from Mecmesin, UK. The test is performed by shaping the dosage form as a rod and applying pressure to the rod. This pressure is increased until the rod breaks. This parameter is referred to as compressive strength and should be understood as the breaking strength under pressure.

  The strength obtained for this dosage form must be maintained for a time sufficient to be transported, stored and sold until the dosage form is used. Thus, at least 95% of the strength of the dosage form should be maintained after 6 months at ambient temperature, preferably after 12 months. Not only is the dosage form stable over time with respect to its biological activity and structure, it is also important that the strength is not substantially affected by storage.

  According to this embodiment, the dosage form can act like a needle and is introduced subcutaneously or submucosally through the patient's dermis and mucous membrane in a manner similar to a hypodermic needle. Thereby, less force is required for the dosage form to penetrate the dermis or mucous membrane, and only a smaller amount of binder is required to obtain the required strength.

  According to a particularly preferred embodiment, as defined above, the dosage form is substantially cylindrical and has one pointed end.

  <Dosage Form> Any kind of therapeutic agent can be incorporated into this dosage form, and the present invention is not limited to drugs with any particular function. Therefore, the therapeutic agents are analgesics, anti-anxiety agents, anti-arrhythmic agents, antibiotics, anti-cholinergic agents, anti-depressants, anti-diabetic agents, antiemetics, anti-histamines, anti-hypertensive agents, anti-inflammatory agents, anti-migraine agents Anti-parkinsonian, anticonvulsant, antipsychotic, antithrombin, antiviral, appetite suppressant, blood factor, cardiovascular agent, cerebral vasodilator, chemotherapeutic agent, cholinergic agent, contraceptive, It can be selected from coronary agents, diuretics, growth factors, hormonal agents, immunosuppressive agents, narcotic antagonists, opioids, peripheral vasodilators, sedatives, vaccines, immunogenic agents, and immunizing agents.

  Similarly, the therapeutic agent can be any type of compound such as steroids, hormones, lipids, nucleic acids, nucleotides, oligonucleotides, oligosaccharides, organics, antibodies, peptidomimetics, peptides, polypeptides, polysaccharides, and proteins. Good. In particular, the therapeutic agent can be a peptide, polypeptide, or protein. Indeed, the dosage form may also include a cellular component dosage form, cell, bacteria or virus for immunogenic purposes.

  It is important that the therapeutic agent is evenly distributed throughout the dosage form so that the release of the therapeutic agent begins as soon as the dosage form begins to dissolve.

  According to a preferred embodiment, the therapeutic agent is selected from hormones, antidiabetic agents, growth factors, and blood factors. Preferably, the therapeutic agent is insulin, glucagon, growth hormone, growth factor, blood factor (eg FVII or FVIII, GLP-1, EPO, TPO) interferon, or derivatives of these proteins. Such a protein may be either a naturally occurring protein or a recombinant protein.

  Such dosage forms may be made from the therapeutic agent alone, but it is appropriate to include a binder in the formulation. Any suitable binder as described in the European Pharmacopoeia, Japanese Pharmacopoeia and / or US Pharmacopoeia may be used if it is acceptable for parenteral use. Examples of binders are carboxymethylcellulose (CMC), fructose, glucose, sucrose, sorbitol, maltose, hydroxypropylcellulose, lactose, D-mannitol, MCC, HPC (hydroxypropylcellulose, Na-phosphate, K-phosphate, Ca-phosphate Na-carbonate and Ca-carbonate.

  Apart from the binder and therapeutic agent, the dosage form may contain additives, which can be selected from the group of preservatives, stabilizers, adjuvants, lubricants and disintegrants, including It is not limited. Although only required in very few examples, some therapeutic agents require the use of preservatives or stabilizers to preserve or stabilize due to the almost anhydrous conditions of the dosage form. might exist. Where the therapeutic agent is for immunization, it is preferred to add an adjuvant to increase immunogen responsiveness. Lubricants such as fatty acids or salts thereof may be added to ensure that the dosage form does not stick to the package, such as a cartridge, and / or to provide lubricity as a dosage form that penetrates the skin. The lubricant may be a stearate such as Mg stearate, Zn stearate or Ca stearate. If rapid release of the therapeutic agent is desired, and if the therapeutic agent occupies the majority of the dosage form, it is necessary to add a disintegrant to disintegrate the dosage form and release the dosage form quickly. It may be.

  The dosage form may also contain stabilizers such as alanine, histidine and glycine.

  Furthermore, the dosage form may be provided with a coating after compression. Such a coating can include, for example, a lubricant as described above, the purpose of which can be, for example, to reduce friction when penetrating the epithelium and reduce injection pain.

  There are several advantages associated with using solid phase dosage forms according to the present invention for parenteral injection. By avoiding needles, one cause of cross-contamination in hospitals is eliminated. The injection volume according to the present invention is very small and can be less than 5 μL, preferably 1-2 μL. Thus, this dosage form can be injected substantially without pain.

  In addition, the therapeutic agent in dosage form according to the present invention is stable over long periods of time even at ambient temperatures and does not require special storage conditions such as refrigeration. Furthermore, this dosage form is also stable at room temperature in terms of compressive strength, binder glass properties and shape.

  The dosage form is preferably used for patients requiring frequent pharmaceutical administration, such as diabetes. Frequently means that the therapeutic agent must be injected parenterally at least once a day. Such patients always need to carry a certain amount of therapeutic agent for injection. The convenience in administration of the dosage forms according to the invention, as well as the convenience of storage, is particularly useful for this group of patients.

  Another preferred use of this dosage form is immunization. Although immunization of children is frequently performed in a general practitioner's office, they will understand that the storage requirements of the dosage form according to the present invention are not strict. The same cartridge containing several dosage forms can be used for different children because there is no risk of cross contamination. The only object that penetrates the patient's skin is the dosage form itself. The injection will not contaminate the injection device or the cartridge housing containing the dosage form. In addition, children who frequently suffer from fear before injection will understand that almost painless injections can be made.

  Another large group of patients in need of immunization is in an endemic area in the tropics, in which case large populations need to be immunized essentially simultaneously. Using a dosage form according to the present invention for mass immunization is much faster and much safer than using conventional injections of aqueous solutions or suspensions of immunoactive agents. According to the prior art, it is necessary to use a new hypodermic needle for each person.

  Large doses are often used in animal and fish breeding. In these cases too, it would be a great advantage to use the dosage form according to the invention for reasons of speed and reduced cross contamination.

  Next, the apparatus will be described in detail with reference to the drawings.

  FIG. 1 shows a first roller 1 according to the invention. A plurality of cavities 2 are arranged on the peripheral surface of the roller 1. The distance between two adjacent cavities 2 ', 2' 'is represented by 3. In FIG. 1, the cavities 2 are uniformly arranged along the circumference. That is, distance 3 is the same for all adjacent cavities 2.

  FIG. 2 is a schematic view of a double roll press apparatus according to the present invention, which includes a first roller 1 and a second roller 4. The first roller 1 is similar to that described with respect to FIG. The second roller 4 includes a secondary cavity 5. The two rollers are arranged so that each cavity 2 takes a secondary cavity 5 when the two cavities rotate in opposition, so that the combination of cavity 2 and secondary cavity 5 It is possible to produce dosage forms defined by In this example, the shape and dimensions of cavity 2 and subcavity 5 are the same, but as explained above, this is not necessary for all devices.

  FIG. 3 is a schematic view of the first roller 1, on which cavities 2, 2 ″ are seen. In this figure, an elongated cavity 2 is shown. The distance between two adjacent cavities 2, 2 '' is indicated by 3.

  FIG. 4 depicts a first roller 1 comparable to that of FIG. 3, the difference being that the distance 3 is much smaller than that of FIG.

  FIGS. 5 and 6 show schematic views similar to FIGS. 3 and 4, except that in FIGS. 5 and 6 the cavity tapers to the tip 6.

Claims (66)

A method for producing an elongated dosage form comprising:
Placing a first roller proximate to a surface, forming a cavity between the first roller and the surface, the cavity defining a shape of the dosage form;
Supplying drug granules into the gap between the first roller and the surface;
Rotating the roller against the surface to thereby apply pressure to the drug granules to form the dosage form in the cavity;
Separating the first roller from the surface;
Releasing the compressed dosage form from the pocket cavity;
Comprising a method. The pressure applied to the drug granulate is 25~5000 kg / cm ^2, preferably 100~1000 kg / cm ^2, The method of claim 1. The method according to claim 2, wherein the density of the uncompressed drug granules is 0.1 to 0.1 g / cm ³ .   The method according to claim 1, wherein the cavity is a pocket cavity formed in the first roller.   The method of claim 4, wherein the pocket cavity is formed in a protruding portion of the first roller.   The method according to claim 4 or 5, wherein the surface comprises at least one subcavity, and the shape of the dosage form is defined by the pocket cavity and the subcavity.   7. A method according to any one of the preceding claims, wherein the elongate dosage form has a substantially circular cross section and the diameter of the formulation is 0.2-1.0 mm.   The method according to any one of claims 1 to 7, wherein the ratio of the average diameter of the drug granules to the cross-sectional diameter of the dosage form is 1: 2 or less, preferably 1: 4.   The method according to any one of claims 1 to 8, wherein the dosage form has an average diameter of 10 to 250 µm, preferably 250 to 150 µm, more preferably 25 to 100 µm.   10. A method according to any one of the preceding claims, wherein the density of the compressed drug orientation is at least twice, preferably at least 2.5 times the density of the uncompressed drug granules.   11. The ratio of the length of the elongated dosage form to the diameter of the elongated dosage form is 100: 1 to 3: 1, preferably 20: 1 to 5: 1. The method described.   12. The method according to any one of claims 1 to 11, wherein the elongated dosage form has a length of preferably 1 to 20 mm, more preferably 2 to 10 mm.   13. A method according to any one of the preceding claims, wherein the elongated dosage form comprises a point.   14. A method according to claim 13, wherein the tip tapers at an angle of less than 90 [deg.], Preferably less than 75 [deg.], More preferably less than 60 [deg.].   15. The method of claim 14, wherein the radius is reduced by at least 30% from one end of the tip to the other.   The method according to claim 6, wherein the internal shape of the subcavity is substantially the same as the internal shape of the pocket cavity.   16. A method according to any one of claims 6 to 15, wherein the internal shape of the pocket cavity defines a portion that is more than half of the external shape of the dosage form.   18. A method according to any one of the preceding claims, wherein a portion of the interior shape of the pocket cavity defines a portion that is more than half of the external shape of the tip of the dosage form.   19. A method according to any one of the preceding claims, wherein the surface is the surface of a second roller, whereby the first roller and the second roller function as a double roll press.   The method according to any one of claims 4 to 18, wherein the surface is part of a conveyor belt.   21. A method according to any one of claims 1 to 20, wherein the pressure is applied to the drug granule prior to delivery.   The method according to any one of claims 1 to 21, wherein the pressure is applied to the dosage form while it is being supplied.   23. A method according to claim 21 or 22, wherein the pressure is applied by a screw feeder or a pressure piston.   24. A method according to claim 21, 22 or 23, wherein the drug granules are compressed into a rod before being fed into the gap.   25. A method according to any one of claims 1 to 24, wherein the first roller is continuously rotated against the surface.   25. A method according to any one of the preceding claims, wherein the first roller is rotated in stages, whereby a rotation / compression step is performed after the feeding step.   27. A method according to any one of the preceding claims, wherein the compressed dosage form is released by vacuum suction.   28. A method according to any one of claims 1 to 27, wherein a destroyer is provided inside the pocket cavity to release the compressed dosage form from the cavity.   29. The method of claim 28, wherein the destroyer is located in the middle of the cavity.   29. The method of claim 28, wherein the destroyer is disposed at one end of the cavity.   27. A method according to any one of the preceding claims, wherein the compressed drug orientation is demolded by a continuous band lining each pocket cavity or subcavity.   32. A method according to any one of the preceding claims, wherein the first roller comprises at least two, preferably ten or more pocket cavities.   33. The method of claim 32, wherein the shortest distance between the centers of the two adjacent cavities corresponds to at least the diameter of the dosage form, preferably at least 1.2 times the diameter of the dosage form.   34. A method according to any one of claims 1 to 33, wherein the diameter of the first roller is at least 1 cm, more preferably at least 4 cm.   35. A method according to any one of claims 1 to 34, wherein the cavity is heated to a temperature above room temperature during the production of the dosage form.   36. The method of claim 35, wherein the cavity is heated and subsequently cooled during manufacture of the dosage form. An apparatus for producing an elongated dosage form comprising:
A first roller disposed adjacent to the surface so as to form a cavity with the surface;
Means for supplying drug granules into the gap between the first roller and the surface;
Means for rotating the roller against the surface and compressing the dosage form in the cavity;
Means for removing the first roller from the surface;
Means for releasing the compressed dosage form from the pocket cavity;
A device comprising:   38. The apparatus of claim 37, wherein the cavity is a pocket cavity provided in the first roller.   40. The apparatus of claim 38, wherein the pocket cavity is disposed in a protruding portion of the first roller.   41. The apparatus of claim 39 or 40, wherein the surface comprises at least one subcavity, and the shape of the dosage form is defined by the pocket cavity and the subcavity.   41. A device according to any one of claims 37 to 40, wherein the elongate dosage form has a substantially circular cross section, and the diameter of the formulation is 0.2 to 1.0 mm.   42. The ratio of the length of the elongated dosage form to the diameter of the elongated dosage form is 100: 1 to 3: 1, preferably 20: 1 to 5: 1. The device described.   42. Apparatus according to any one of claims 37 to 41, wherein the length of the elongated dosage form is preferably 1 to 20 mm, more preferably 2 to 10 mm.   44. Apparatus according to any one of claims 37 to 43, wherein the elongated dosage form comprises a tip.   45. Apparatus according to claim 44, wherein the tip tapers at an angle of less than 90 [deg.], Preferably less than 75 [deg.], More preferably less than 60 [deg.].   45. The apparatus of claim 44, wherein the radius is reduced by at least 30% from one end of the tip to the other.   47. An apparatus according to any one of claims 40 to 46, wherein the internal shape of the secondary cavity is substantially the same as the internal shape of the pocket cavity.   47. The device according to any one of claims 40 to 46, wherein the internal shape of the pocket cavity defines a portion that is more than half of the external shape of the dosage form.   47. Apparatus according to any one of claims 40 to 46, wherein a portion of the internal shape of the pocket cavity defines a portion that is more than half of the external shape of the tip of the dosage form.   50. Apparatus according to any one of claims 37 to 49, wherein the surface is a surface of a second roller, whereby the first roller and the second roller function as a double roll press.   49. Apparatus according to any one of claims 37 to 48, wherein the surface is part of a conveyor belt.   52. Apparatus according to any one of claims 37 to 51, wherein means are provided for applying pressure to the drug granules prior to feeding into the gap.   53. The apparatus of claim 52, wherein the pressure is applied by a screw feeder or a pressure piston.   54. Apparatus according to claim 52 or 53, wherein the drug granules are compressed into a rod before being fed into the gap.   55. Apparatus according to any one of claims 37 to 54, wherein the first roller is arranged to abut against the surface and rotate continuously.   55. Apparatus according to any one of claims 37 to 54, wherein the first roller is arranged to rotate in stages.   57. Apparatus according to any one of claims 37 to 56, wherein means for vacuum suction are arranged as a destroyer.   57. Apparatus according to any one of claims 37 to 56, wherein a destroyer is provided in the pocket cavity for releasing the compressed dosage form from the cavity.   59. The apparatus of claim 58, wherein the destroyer is located in the center of the cavity.   59. The apparatus of claim 58, wherein the destroyer is disposed at one end of the cavity.   61. Apparatus according to any one of claims 37 to 60, wherein continuous bands line each pocket cavity or subcavity.   62. Apparatus according to any one of claims 37 to 61, wherein the first roller comprises at least two, preferably ten or more pocket cavities.   63. Apparatus according to claim 62, wherein the shortest distance between the centers of the two adjacent cavities corresponds to at least the diameter of the dosage form, preferably at least 1.2 times the diameter of the dosage form.   64. Apparatus according to any one of claims 57 to 63, wherein the diameter of the first roller is at least 1 cm, more preferably at least 4 cm.   65. An apparatus according to any one of claims 37 to 64, wherein the cavity is further heated to a temperature above room temperature during manufacture of the dosage form.   66. The apparatus of claim 65, wherein the cavity is adapted to be heated and subsequently cooled during manufacture of the dosage form.

Images