KR800001089B1 - Prcess for preparing novel web dosage form - Google Patents

Abstract

Pharmaceutical dosage forms are made up with an edible web containing a particulate medicament. The web is fabricated for pharmaceutically elegant solid dosage forms having no medicament exposed on an exterior surface. The disclosed solid dosage forms aew prepared with high-speed automated equipment and the process by which they are made is characterized by non-destructive quality control analysis and performance evaluation both conducted on-line and integrated into the manufacturing operation.

Description

Method of Preparation of Reticulum Formulation

Figure 1: Total Milestones

Figure 2: Mechanical drawing to enable the process of Figure 1

3: A drawing on the method of assembling the formulation wound in a new type

4, 4a and 5: the formulation of the formulation by the lamination process

Figures 6a to d: a diagram relating to the final step and the sealing step of the formulation assembly by the pan-folding method

7 and 8: A diagram of the active ingredient release pattern of the formulation according to the present invention compared to the capsule

The present invention relates to a process for the preparation of a novel pharmaceutical solid dosage form (web).

Previously orally administered unit dosage forms are generally two major forms in pharmaceuticals, both technically, tablets and capsules, both of which have a wide range of broad ranges. Enteric-derived releases, extended release of drugs by various mechanisms, effervescent tablets, and the like. Usually these solid oral formulations present a number of inconveniences.

First, these conventional oral unit dosage forms have the disadvantage of mixing the active ingredients with various substances called pharmaceutical inert or nontoxic pharmaceutical additives. Such materials include diluents, excipients, binders, lubricants, disintegrants, stabilizers, buffers, preservatives and the like. Although these substances are indispensable for pharmaceutical preparations, their use poses a problem that must be handled in terms of price, final size and unit weight. Such substances, such as more suspending agents, present problems with the physiological use of the active ingredient. Incorporation of these substances should also be considered in the analytical methods used to determine the titer of the final formulation.

A second important disadvantage with conventional solid oral unit dosage forms is that methods useful for analysis break down such formulations and only test a small amount of such formulations actually produced. Therefore, technically, even within a batch of a batch, given the difference in each batch, a relatively small sample may be taken and analyzed to yield an average value, which can be quite different.

The batch dog itself is a disadvantage in the conventional oral solid formulation only in light of the economics of the design, adjustment and evaluation of the batch.

Since the solid dosage form according to the present invention is prepared by a method unique to the pharmaceutical field, it is possible to produce a large amount of solid form mainly for oral administration at a rapid rate, and solid oral dosage forms which have recently been useful as tablets or capsules. Of the above, many of the disadvantages described above do not suffer from difficulties. This method has the following high advantages:

(1) This method eliminates the need for batches required for conventional methods,

(2) It is possible to analyze the activity of the formulation by the on-line method as well as the potency analysis by the continuous on-line method during manufacture.

(3) There is virtually no need for mixing with conventional pharmaceutical adducts, except for glidants and / or any other materials useful for manufacturing operations necessary to increase the flowability of the powder.

(4) Pharmaceutically superior unit dosage forms can be prepared that can produce faster release rates than commercially available tablets and capsules and are ready to release the drug at any desired rate.

In summary, it can be assured that the formulations according to the invention are more usefully used in a more accurate control time after digestion than in the case of current commercial unit dosage forms.

The oral unit dosage form according to the invention is useful in view of the fact that the situation is analyzed substantially by the on-line method during a substantial automated manufacturing process which proceeds at a rapid pace and the dosage form according to the invention is also a drug contained therein. It is also useful in terms of release absorption with exceptional consistency for most of these formulations. Moreover, the formulations according to the invention can be prepared to, after administration, release the drug in less time than solid oral formulations such as tablets and capsules currently available may have. Therefore, the unit dosage form according to the present invention has better uniformity in terms of drug content and release for absorption.

Conventional literature on solid formulations distinguishing from conventional tablets is as follows. Russell describes a carrier for oral administration of a drug made of a small piece of gelatinous material containing a drug in US Pat. No. 3,444,858, issued May 20, 1969, each of which may be easily torn off. It is divided into parts by connecting to the next one with a line. In reality, each part is separated from a small piece just by putting it in your mouth.

Secondly, the literature on which it is based is the article described in the references. [Reference: New England Journal of Medicine Vol. 289, No. 10, pp. 533-5 (1973)]

This article describes a method for administering a woman's drug in large quantities to women in the People's Republic of China. This method is to treat a sheet of colored water-soluble carboxy methylcellulose species with a progesterone substance and an estrogen substance. Then cut a hole in the paper and cut it into pieces. The drug is packaged as 22 square pieces that are cut into pieces and eaten daily. This method does not conceal the drug in the final formulation, which, once opened, results in disadvantages of potency contamination and / or inactivation of the drug. Moreover, these pieces, which are perforated because they are not fully integrated, are torn unevenly and do not have a constant capacity in terms of titer.

Finally, in the US Patent No. 3,625,214 to Higuchi et al., Issued December 7, 1971, there is a description of a controlled dosage form such as a sustained release formulation. The focal point of this formulation is that it has a mold that is coated on a substrate and then spirally wound to form a "jelly roll". After ingestion, the drug is released as the outer skin of the substrate gradually corrodes, and also diffuses from the side to which the drug is exposed. There is no announcement of how this formulation to be mass produced can be mass produced, and moreover, there is no announcement of how to make this published formulation a pharmaceutically good final product.

Contrary to what is disclosed in the above, the novel solid unit formulations according to the invention are fully integrated, unbroken and capable of performing analytical tests by on-line methods during the rough production of pharmaceutical preparations and hindering their action. No additives are necessarily required, and the drug is not directly exposed and the drug release is excellently constant, enhancing the efficacy of the drug.

Solid unit dosage forms for oral administration have been published which consist of reticulum, an edible paper and / or polymeric substance, loaded in whole or in part with one or more drugs that do not necessarily incorporate a pharmaceutical adduct, which is ingestible. It is assembled in such a way that it is sealed in a shape suitable for pharmaceutical or cosmetic so as not to expose the drug. Unit dosage forms are prepared by methods of mass production of pharmaceutical preparations using new machinery. The manufacturing process includes a test apparatus that quantifies the amount of drug loaded into the reticulum before assembling the final unit dose potency assay using physical instruments without breaking the formulation on-line.

The present invention is directed to a method for preparing solid unit dosage forms for oral administration, which is more useful in many ways than current solid oral dosage forms such as tablets and capsules.

First, the unit enactment of the present invention is substantially free of conventional pharmaceutical additives, resulting in cost and manufacturing process costs and eliminating incompatibility due to the incorporation of such materials. There is a clear difference between the reticulum, which can be considered as an adduct in the present invention, and materials such as fillers and binders that are mixed with the drug in conventional solid dosage forms.

Secondly, the solid unit dosage forms of the present invention can be prepared continuously and can be analyzed without on-line disintegration, thus eliminating the need to produce batches, which has significant economic benefits and substantially quality control in finished unit dosage forms. Can improve the level. The manufacturing process of the present invention has a device for returning information from the test site to the manufacturing process to be corrected and adjusted on-line to enter the process soon again. Such a device removes only a small amount of the unit dosage form from any number indicated in one batch, ie, what appears as a plus is immediately negative and then becomes a plus.

This avoids “poisoning of the barrel” due to the small labeling and removal of these formulations and is particularly superior to many economics and active ingredients in final formulations compared to current pharmaceutical manufacturing processes. It can be seen that the level of substance management is simultaneously increased. In normal operation, the formulations of the present invention are prepared by a time formulation, ie, a batch of formulation means the number produced between two points given in time. However, as a final product testing, some drug manufacturing processes may require disintegration testing. However, the method of the present invention requires such testing to a much lesser extent than conventional manufacturing. More importantly, however, it is possible to benefit from the above described decay test because the decay test, such as the evaluation of action, is often checked and returned back on-line.

Third, the solid oral dosage form of the present invention is unique in form, form, assembly, and the like, unlike conventional tablets and capsules, and therefore has the advantage of being easily distributed. In addition, the non-destructive test process and the continuous manufacturing process by the on-line method of the present invention is made of a transparent plastic plate for packaging in which individual units of the unit dosage form according to the present invention are foamed by the on-line method. It can be packaged in containers, thus reducing costs in terms of handling and equipment.

Fourth, the specification of the size, shape, release of the drug, etc., because the accuracy of the preparation of the solid dosage form of the present invention, that is, the shape of the final unit dosage form in which the drug is constantly loaded onto the network and the network itself has desirable characteristics is correct. This makes it easy to specify the final formulation. In addition, the formulation according to the present invention has excellent stability, and the load on the reticular body of the drug is an electrical contact, which can also be mixed with the drug which may cause a reverse reaction by water, and is also manufactured in several layers of reticular chemically compatible. Drugs involved in the incorporation of drugs that can not be made can be prepared by loading one to each of the reticulum. This effectively results in economic losses such as combining such combinations with one or more incompatible materials with an insulating material, mixing these drugs with stabilizing adducts, or tableting these drugs separately and multilayering them. It makes it stable without the need to operate it.

One or both of these operations, namely the electrostatic loading of the drug into the network as a dry powder, and the loading of the drug incompatible in terms of titer, by the filtering between the layers of each layer of the network, can lead to the formulation according to the invention. It can be used very useful also in administration of foaming agent.

Solid oral formulations according to the invention are also unique in that the drugs contained therein are usually completely released into the formulation, without the original coating being applied to the final formulation. This suggests that the formulations according to the invention have additional economical advantages, whereas the conventional tablets must be coated to obtain an internal release of the drug.

Formulations prepared according to the process of the invention are mainly used for oral administration and are likewise used in formulations suitable for rectal and / or vaginal administration. Changes in size in the network as well as the assembly methods described later to produce formulations of the desired size and shape are properties that can be easily made by a professional. Similarly, in order to obtain the desired form and pattern on the drug release surface, the composition of the network can also be modified. The solid formulations according to the invention were tested by insertion into the rectum and vagina with no substantial local irritation.

As mentioned above, the novel unit dosage forms prepared according to the present invention may be formulated or treated with any desired release form, including sustained release forms. Irrespective of the release pattern, the unit dosage form of the present invention is characterized by an exceptionally constant release for a large number of unit dosages of only one or more. The change in release rate can be obtained by manipulating various factors, such as the thickness of the network, the composition of the network, the shell or composition of the assembled network, or the density of the network assembly in accordance with the present invention. For example, a reticular composition containing a large amount of sodium carboxymethyl cellulose is slowly and slowly disintegrated in gastric juice. When the formulation of the reticular body assembled by the fam-folding method described below is contacted with gastric juice, the loaded drug is released very rapidly from the inner surface, and thus, tablets and capsules which are generally used in practice in practice today It will release much faster. However, when such a pan-folded formulation is sealed with a substance such as ethylcellulose, cellulose acetate phthalate or corn protein, which prevents splice in gastric juice, the drug is gradually released and used as the reticulum is corroded when sealed on the folded edge. It becomes possible.

This release pattern represents the preferred content of the present invention because the formulations prepared according to the present invention release the drug at a much faster rate than the current useful solid formulations such as conventional tablets and capsules.

The reticulum, which is able to load and use the drug according to the present invention, must have many physical and chemical features that are acceptable in the present invention. A summary of these criteria is as follows.

The reticulum should be non-toxic, edible, and not particularly heterogeneous in the mouth. Furthermore, the reticular body is preferably capable of decaying on its own or in body fluids and / or enzymes, but may also be a non-degradable material that is easily removed, preferably hydrophilic, and easily disintegrated in water. This property is not counterproductive and it is desirable that the action is elevated at the pH of the gastric juice:

The reticular body should not release any substance when dissolved in gastric fluid which is inert to the drug loaded on it and which is incompatible with the drug originally mentioned in itself.

The reticular should be stable at high temperatures, high relative humidity for a long time and generally should not be suitable as a medium for microorganisms.

The network should have as much resistance as possible to regularly load the powdered drug (usually of genetic nature) into the network.

The reticular body must have flexibility and mechanical properties, that is, have sufficient elasticity to be pulled out into thin paper with a thickness of 0.025 to 0.25 mm, have good tension and tearing properties, and endure the assembly method described later. It must have sufficient durability against the required creases.

The reticular surface should be easy to shape the analytical process by the on-line method described below, and should be able to load coating, electrostatically or powdered drugs by other means, You should be able to.

The network should be sealed easily or by a liquid or heat sealing method that is acceptable in the art, but this sealing method should be effective against moisture and heat to the extent that it will not adversely affect the drug contained in the formulation. In addition, the reticular body must be flame retardant to withstand the sealing process.

In some cases, the reticulum must have some sort of "reversibility," that is, with sufficient elasticity, in contact with the gastric juice, it is necessary to reverse and expose the assembly process very quickly to enable drug release for absorption. By exposure, for example, if the formulation is assembled by pan-folding, it will open like a corrugated container, and if the assembly is by way of outboard winding, the coil will be loosened.

The reticular body should have properties such as acceptable taste and smell that are familiar to those familiar with this presentation.

As mentioned above, the network used in the present invention is preferably soluble in water or dispersible in water. There are two basic mechanisms for formulating the network according to the invention to decay on its own in contact with water or gastric juice. First, the network contains particles of a substance such as casein gelatin, which can swell in contact with water to collapse or break the network. Second, the reticular preparations contain both soluble and insoluble components in water. Upon contact with water, the soluble components of these preparations dissolve to form a solution, and the insoluble components precipitated here disrupt the network. The latter meaning of reticulum collapse is not as quick as the former. Examples of suitable water-soluble components include methyl cellulose and the like, and examples of suitable water-insoluble components include ethyl cellulose and the like.

The network preparations used to prepare the novel formulations of the invention come in two basic forms: polymers or paper. Polymer formulations generally contain the following:

a) at least one organic film former

b) one or more plasticizers

c) any other ingredients in certain formulations such as modifiers, ie disintegrants, weights and the like.

d) one or more volatile solvents

Paper formulations generally contain the following:

a) at least one fibrous material

b) at least one non-fibrous modifier, that is, any other component that is present in any formulation, such as at least one organic film former, disintegrant, weight agent, and the like.

c) rare solvents

The film-forming compounds of the polymer network of the polymer according to the present invention include a homogenous, generally technically recognized and nontoxic organic film former, for example, natural or synthetic starch dextrins, proteins such as gelatin, sodium carboxy Cellulose derivatives such as methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose and the like, polysaccharides such as pectin, acacia, xanthine gum, guar gum and algin, or polyvinyl pyrrolidone, such as polyvinyl alcohol Synthetic materials; Preferred film formers are hydroxy propylcellulose and sodium carboxy methylcellulose. Although the concentration of the film former in the polymer network is not particularly important in practice, the concentration is preferably between about 5 and 95% by weight and most preferably between 40% and 90%. The above mentioned film forming material is the same as the film forming material of the network reticulated body according to the present invention. Preferred film formers of the paper-like network preparations according to the invention are likewise hydroxy propylcellulose and sodium carboxymethyl cellulose. The concentration of the film-forming component in the paper network of the present invention is also not important as in the above. However, since these components act as binders or disintegrating agents of the fibrous material, they should not exceed 40% by weight, preferably about 2 to 20% and most preferably about 4 to 10%.

As the fibrous component of the paper-like network according to the present invention, any of commercially available natural or artificial fibers which are nontoxic in a proper test can be used.

Examples of such fibers include cotton, flax, cellulose, semisynthetic cellulose, rayon, woven vegetable protein and collagen.

In order to ensure the desired flexibility and mechanical properties, the polymer network used in practicing the present invention contains an effective amount of plasticizer. Such components include one or more plasticizers that can be understood in terms of pharmaceutical mixing techniques, for example mono- or di-glycerols of polysorbate-type fatty acids such as glycerin, polysorbate 80, polysorbate 60, etc. Mixtures of rides and the like. Such plasticizers preferably contain an amount of about 1% to 60% by weight, more preferably about 10% to 50% of the network composition.

Both polymer and paper reticulates may contain one or more disintegrants commonly understood in the paper art, such as various starches, casein, gelatin and the like. It is preferred that the network according to the invention should contain from about 0 to 40% disintegrant of the network preparation and contain from 5 to 20% by weight.

Furthermore, both forms of reticular preparations may contain one or more fillers or weighting agents as would be understood in the art. For example, these components include milky fillers such as titanium dioxide, kaolin, microcrystalline cellulose and calcium carbonate. Some of the components specified herein fall into one or more of the above categories as they may serve more than one action. Calcium carbonate, for example, acts as both a bleach and a dispersant, and some starches have both a binder and a disintegrant.

In addition, all formulations of polymerizers and papers may contain one or more regulatory ingredients that affect the electrical, mechanical, optical, or permeability of the network prepared therefrom. Examples of such components include electrolytes such as sodium chloride, potassium chloride and the like, surfactants such as dioctyl sodium sulfosuccinate and the like.

The network may also optionally contain pharmaceutically harmless ingredients such as colorants, preservatives and the like.

Finally, both forms of reticular preparations usually contain volatile solvents that are removed during the preparation of the reticular preparations, such as water, organic solvents such as ethyl alcohol, or mixtures of solvents such as aqueous alcoholic solutions.

Particular examples of film compositions according to the invention are as follows:

Polymer film that decays itself due to the presence of swelling agent in water

Both formulations (I)-(IV) can be sealed using heat and pressure. The formulation (IV) itself decays itself in the accepting state due to the presence of an insoluble polymer.

Preferred paper formulations according to the invention contain from about 70 to 99% (by weight) of fibers, such as hard wood or soft wood fibers or mixtures thereof, more preferably from about 90 to 96% and more preferably from about 1 to 30% More preferably about 4 to 10% containing disintegrant. Disintegrants include sodium carboxy methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone or guar gum, containing about 0% to 5% surfactant, preferably about 0 to 2%, and the surfactant is poly Solvate 80, dioctylsodium sulfosuccinate, sodium laurylsulfate, and the ability of these materials to act as disintegrants in paper formulations, in which the materials of the group are used in various amounts to make paper. In terms of letting the outside is out. For example, a small amount of sodium carboxymethyl cellulose used to make paper is used to help disperse the fibers, i.e. less than 0.1% (by weight) when making paper. In contrast, the sodium carboxy methyl cellulose or other substances listed above should be added in large amounts up to 30% (by weight) after the preparation of the paper reticulum, but the addition of these substances during humid periods acting as a disintegrant. Time is important for acting as a disintegrant. The disintegrant is preferably added in a solution state dissolved in the solvent used to produce a paper network. It was found that when the above-mentioned disintegrant is added to the above-described network, the disintegrant coats the fiber. When the final formulation is brought into contact with water, the disintegrant swells to collapse the fibrous reticulum, and the incorporated surfactant acts to promote disintegration by increasing the permeability of water into the disintegrant.

The network used in accordance with the present invention is produced by a conventional manufacturing process such as papermaking industry or film production industry. For example, polymer reticules may be molded into suitable substrates such as Mylar, stainless steel, release paper, and the like. The network is then dried in an air blow oven. The temperature of the drying air and the length of drying time depend on the nature of the solvent used, as can be understood in the art. However, most of the reticular bodies in the present specification are dried at a temperature of 25 to 105 ° C., and a temperature of 60 to 90 ° C. is preferable.

The second method for producing a network of ordinary polymers is extrusion. This method is preferred for networks where the film forming material is an improved edible starch, hydroxypropyl cellulose or other extrudable polymer. The mechanical features of the extrusion method, i.e. the unique use device, the extrusion force and the shape and temperature of the holes, should be considered in technical terms and can be varied by known methods to achieve the physical properties of the network described below.

The paper network according to the present invention is produced using a conventional paper making machine, an example of which is a Fourdrinier paper machine. In all cases, however, the reticular must be constant in both thickness and width. The reticular body is about 1 to 10 milligrams (about 0.03 to 0.3 mm), preferably about 1.5 to 4.5 milligrams (about 0.038 to 0.123 mm) and the width of the reticular body is not critical in the practical sense of the present invention. It is convenient to be 12 inches (30 cm). The network can be manufactured to any length. However, in the light of the fact that the new formulations prepared according to the invention are mainly suitable for high speed production, the reticular bodies have to be prepared in large quantities, for example, to more than 15,000 feet, which can be stored and stored in fail-like packages.

Reference will now be made to FIG. 1, which is a diagram of a unit process for the production of the various types of formulations described herein in large quantities. Column 10 in FIG. 1 is a process for preparing the network used in the formulation as described above. During or shortly after the manufacture of the network, the next step, check (section 11 in Figure 1), is carried out through various automated tests, in part or in whole, to confirm the integrity of the network, which will be described in more detail below. However, it should be noted that the inspection of the reticular body is carried out by a device or other device connected to the reticular manufacturing apparatus at the time of manufacture of the reticular body or at a convenient time, and actually by being installed elsewhere.

The active ingredient to be loaded onto the network is prepared and stored in the container device described in (22) of FIG. 2 for use in various devices suitable for the process described in FIG. The active ingredient prepared in No. 12 of FIG. 1 is transferred to the apparatus (23) of FIG. 2 to reduce and control the particle size of the active ingredient. Although this process is described in more detail later, the device indicated by (24) of FIG. 2 is loaded with the active ingredient to the correct and constant network through step 13 of FIG. 1, that is, device (23) of FIG. . (No. 14 in Fig. 1), it should be noted that the particulate matter dried in the dry state is loaded by the mechanism described in Fig. 2.

However, the scope of the present invention also includes the wet load method of the active ingredient into the network. FIG. 2 also diagrammatically performs a separate inspection of the reticular body manufactured in device 21 and the stored reticular body for use after being wound on the storage roll 20, i.e., the reticular check (step 11 in FIG. 1). Indicates. It is clearly understood that the check is carried out with the device indicated in Figure 21 of Figure 2 before or during winding up the network. The details of the network check will be described later in more detail.

In more detail with regard to inspection apparatus 21, inspection of uncoated reticular bodies is carried out by various methods. The integrity of holes, defects, and physical properties of the network can be assessed and quality controlled using a combination of laser beam scanning and photodet-ctor. The device uses both transmission and reflection. A continuous helium-neon laser beam is passed through the network by a mirror on the galvanometer. The position of the mirror is electrically controlled so that it can be placed in the groove of the reticular body. The reflected or transmitted light is detected by a straight line photodiode placed behind the obstruction filler to block light in the room.

The electrical output allows the calculation of the number of defects and the allocation according to the size of the network and the length of the network. This is done by analyzing the detector output signal shown in the plus height-width analyzer.

An alternative way to check the network at much higher speeds is to place photodiodes placed parallel across the network. Each photodiode has its own starting point detector and a digital characteristic of the size and position of the groove with low resolution. The output signal provides an overview of the size distribution and the location of the grooves.

The physical thickness of the network is measured by arranging the scaled riders in parallel. The roller is in contact with the reticular body and is electrically connected to a force-transmitting device that is sensitive at least 1 / 10,000 inches.

A similar physical thickness measurement device can be made of an airborne sensing device that floats the reticular body onto a fixed film of air. This device has the advantage of not being in direct contact with the network.

Mass thickness (weight per unit area) or the basis weight of the reticular body is measured by using the β-ray or X-ray proximate without contact.

This device measures the absorption of β-rays or X-rays through the network. This absorption is related to the mass thickness. Another device is to use the electrical resistance between the two contacting nets and the electrodes to measure the basis weight of the nets with known moisture content.

On-line analysis of the water content can be analyzed by measuring with one or more of the following devices. First, the high dielectric constant of water is used to measure the absorption of microwaves and the sensitive moisture content by the RF detector. Low frequency conductivity measuring instruments can also be used to measure moisture content. The method by absorption in the infrared spectrum is an independent water measurement method as a whole. In addition, the method by optical absorption in the wavelength of 1-2μ is a method that can measure a specific and accurate moisture near this wavelength when the network to be checked is relatively transparent.

The network passed through the inspection device 21 is passed very close to the active component loading device 24 which is carried by the appropriate roller device in FIG. 2 to load the active component onto the network. The loading device is connected to a separate device 25 for on-line analysis / checking to check whether the content of the active ingredient is constant and whether the reticulum coated with a single sheet of paper prior to the inclusion of the active ingredient is preferably constant. .

A preferred method of analyzing on-line without disrupting the active ingredient loaded on the network is X-ray absorption. In this method, a peak of low energy X-rays, which coincides with terminal absorption of atoms loaded on the network, is transmitted directly through the coated network. Absorption of X-rays relates to absorption of the active ingredient-reticle. If the active ingredient is loaded onto the network by wet coating, this analytical method can be useful before and after the drying step.

Since total X-ray absorption is for a mixture of the coated network and the active ingredient, it is necessary to separately measure the absorption of the network only. This can be done by a β-ray measuring device or an infrared absorber. The increase in sensitivity can be achieved by X-ray measurement of a loaded active ingredient containing atoms of increasing atomic number. X-ray light sources can be controlled by varying the accelerating voltage to match the terminal absorption for many atoms of interest.

Reflectance or transmittance spectroscopy can also be used to analyze active components loaded by on-line methods without disruption. Reflectance spectroscopy is used to measure the amount of active ingredient loaded near the ultraviolet. This method is used for any solid active ingredient having optical absorption in the appropriate wavelength region.

Transmission spectroscopy can also be used to analyze on-line without disrupting the active ingredient coated on the network. With a suitable light source, monochromatic element and detector, the mixing device selects the wavelength that selectively absorbs the active ingredient. This wavelength must be a wavelength at which the network itself does not absorb strongly. The wavelength region for the network of the present invention is near infrared and infrared due to spectral functional groups. Fast wavelength scanners often cross small wavelength regions of interest. The signal from the detector is the average of several scans to reduce the noise effect. This signal data then leads to the first transmission induction in terms of wavelength for increased sensitivity. This is done in a similar manner for other wavelength regions that are sensitive to other components in the device. Thus, it is possible to simultaneously measure the amount of active ingredient, as well as the moisture content and the net weight of the network.

Another method for the analysis of loaded active ingredients is molecular fluorescence.

Excitation rays of ultraviolet or visible light on the spectrum are produced by a suitable filter mixer. The fluorescence of the active ingredient is detected by matching the wide band filter-detector mixing device to the fluorescence peak, and the blocking filter is used to remove the excitation energy. The detectors of this method are preferred photon counters, which produce individual light quantities with high sensitivity and straightness, even at low light levels. Care must be taken in these assays to prevent photolysis of the active ingredient by excitation light. The coated network is temporarily stored or preferably assembled (16 in FIG. 1) and unitized (17 in FIG. 1) as a series of blades 26 which divides the coated network into a number of endless pieces. It is sent directly to the device to form a formulation and then sent to the assembly and unit of the lamination type (27). In other words, here, endless pieces are stacked on top of each other to form an endless pile that is pressed and ultimately united in accordance with the present invention.

The unit dosage form is then packaged (final FIG. 1 step 18) through the final step with a suitable device shown in FIGS. 28 and 29 of FIG. 2 for subsequent distribution.

Check in conjunction with this step with a suitable inspection device (30 in FIG. 2). The purpose of the final check of individual unit formulations is to clarify the size, shape, completeness, identity, presence and accuracy of printing and the content of the active ingredient. All these checks are done without collapse except for the active ingredient content. In order to analyze the content and action characteristics of the active ingredient, a sample of statistically appropriate unit dosage form is taken in the manufacturing process, and all of the titers and actions such as dissolution characteristics are disintegrated by the solution spectrometry described later. .

Optical scanning devices can be used to check all manufacturing units for size, shape, completeness, identity and presence and printing accuracy. This apparatus is a mold of a light source side photodetector or a TV camera. Computers are used to obtain signals from the optics. Appropriate notation is used to determine whether a unit is acceptable. Another method is to compare the standard shape and the sample shape by a phase comparison method. Another method for 100% inspection can be by optical modification of the shape of the unit dosage form. Fourier strain spectra, power spectra or other suitable strains are compared by computer to similar variations of the standard ones.

Prior to the final step, an on-line analysis step (step 19 in FIG. 1) for dissolution and certain content is carried out in a suitably arranged device, unless otherwise specified, which contains a computer or similar device and is controlled by it. do. The optional extraction method is taken at the end of the manufacturing process one unit dosage form at a time at a rate of 25 to 120 units / minute, with a rate of 40 to 60 units / minute being preferred. Each unit dosage form is then transferred to a conventional automatic weighing device to weigh and store information without decay. The unit extracted arbitrarily is then put into a conventional automatic analyzer. The unit dosage form is placed in a solvent suitable for the active ingredient and stirred at an appropriate rate. The dissolution rate is the value of the active ingredient dissolved in tj minus the amount of active ingredient dissolved in ti divided by tj-ti.

The time interval (tj-ti) is preselected and depends on the drug. Suitable time intervals are from 5 seconds to 2 minutes or more. The sample is then continuously stirred for a sufficient time to ensure that all of the active ingredients are completely dissolved after analyzing the solvent for the active ingredient content. The amount of active ingredient in this assay plus the amounts from samples ti and tj is the total amount of the formulation. This information is also recorded and kept.

If the analysis of the weight, thickness, dissolution rate and drug content of the drug is within predefined limits, the unit dosage form is acceptable. If the above values are not within these limits, the dosage form starts with a negative analysis and then ends with a positive analysis. The prepared unit dosage form is separated for subsequent evaluation.

As will be described later, it can be seen that the apparatus for more inspection functions to be performed in accordance with the present invention is in FIG. Regarding the network inspection step For example, continuous inspection of the network is performed in terms of the color, thickness, continuity, stain, and various defects of the network. This function can be done by electronic and / or optics as well as by actual visual observation.

Inspection of the reticular body is to actually place a flag on the reticular wherever there is a groove or defect. In addition, the device prints automatically each time a defect is found in the reticular body or under operating control, where it indicates what kind of defect is in the reticular body and identifies the shape of the defect, such as holes, black spots, and blemishes.

The device to be printed is actually the same device that tags the original network. Such a device is known, for example, in the fabrication and inspection of fabrics, except that in the case of the present invention the treatment and inspection of the network is carried out in accordance with a good manufacturing process. In addition, the thickness of the network body is measured by the same or additional conventional inspection apparatus. This can be measured visually with the actuator included or with a detection device connected to a rational arrangement with upper and lower limits of the network thickness, where the printout is affected even when the network thickness exceeds this limit, as described above. It will be tagged on the network. One device capable of measuring the thickness of the reticular body is an X-ray or β-ray meter or a similar device capable of measuring the thickness of the reticular body.

In the case of step 13 of FIG. 1 concerning reducing particle size and adjusting fluidity, the checking function is performed by the method described below. Although the loaded network itself according to the invention is checked to find defects and thicknesses, this similar inspection device must follow after the network load of the active material.

For example, the X-ray measuring apparatus can also be applied to the measurement of the loaded network thickness in comparison with the previously measured network thickness which is also unloaded and the thickness can be determined from the amount of active substance loaded on the network. In addition, the scope of the present invention also includes the provision of an actual mass monitoring device for measuring the amount of active ingredient loaded on the network. It should be understood that the inspection of the coated reticle can be done by tracking the coated reticle through the same apparatus that performs the reticular check associated with FIG.

The active material loading device (see No. 14 in FIG. 1) is to provide on-line analysis of the active material loaded on the network to adjust feedback. For example, an electrical signal from an on-line analysis (digital or similar) that analyzes the loading of the active substance (weight of the active ingredient of the coated network) is used as a feedback link to the network during the loading process. Adjust the amount of active ingredient loaded. This feedback signal feeds, for example, a small computer that produces the right signal suitable for the loading process. The correct signal results in an increase or decrease of the active ingredient in order to load an amount which is less than the desired amount. For example, in a dry load process, powder of the active ingredient is introduced into a load device. This ensures that the correct signal adjusts the feed rate and consequently the loading of the active ingredient.

In wet loading processes, the correct signal is used, for example, to vary the amount of coating agent loaded onto the network. For example, the cap between the measuring rollers or between the measuring blade and the load roller is changed in accordance with the change in the amount of active ingredient loaded. Another method of control in wet loading is to change the concentration of the active ingredient in the coating liquid. Two liquid formulations with different concentrations of active ingredient may be mixed in the required proportions to achieve the correct concentration and then the mixing ratio of the two formulations may be varied to precisely control the loaded active ingredient.

The method of mixing the active substances used in the novel formulations according to the present invention is fundamentally different from the method of mixing the active substances used in the preparation of conventional solid dosage forms such as tablets, capsules, dragees, suppositories and the like. The method and apparatus used in the method of the present invention may be different, but the overall main purpose is to load the active substance on the surface of the reticulum which is overlaid with uniformity of hatching, ie exceptional uniformity.

The method of loading the active material used in the present invention is unique and has many advantages over the manufacturing process used in the conventional pharmaceutical field.

In view of the fact that the active material is assembled on the surface of the edible reticulum and assembled completely internally, there is no need for conventional pharmaceutical excipients, fillers, preservatives to mix with the active material, thus reducing costs and more importantly This has led to the solution of the case of incompatible titration and the problem of quality control. According to the present invention, the active ingredient is uniformly loaded onto the network, and then divided into individual basic units by linear or geometric cutting methods, which are substantially superior to batch methods currently used in the pharmaceutical field, and have many types of units. To have a uniform strength of the active ingredient compared to the formulation.

Clearly, in contrast, conventional pharmaceutical processes require the preparation of large quantities of suitable pharmaceutical additives that are therapeutically inert and active, in large quantities and packed into capsules or compressed into tablets. Therefore, using the preparation method of the present invention, it is possible to reduce the excess of active substance of about 5 to 10% (by weight) to about 1 to 5% in order to assure the current branded dose. It will be appreciated that the same very expensive active materials have to be mixed, which results in substantial cost savings.

Finally, the method of loading the active substance into the network according to the present invention can be tested continuously, on-line without physically disintegrating the formulation by means of a physical device, thus making it possible to achieve a superior homogeneity of mass compared to many conventional formulations. It will contain the active ingredient.

The active ingredient may be loaded onto the network in wet or dry form, preferably in dry form. In any case, the active ingredient is loaded in the form of microparticles that are sensitive to the assay described below. The particle size may be on the order of submicrons and may be between 1 and 100 microns. Submicron sized particles have so far been unable to be produced in pharmaceutical tablets without prior application to methods such as granulation, which are too fine and substantially increase the particle size and also require excipients to be added to the actives.

The method of the present invention can use such ultrafine particles without adding the above methods and / or excipients. The active ingredient is an automatically moving manufacturing device which is loaded by coating it very uniformly on the network.

A preferred method of loading the active ingredient into the network in dry form is a powder cloud electrostatic loading method using techniques which are generally readily understood in certain non-pharmaceutical fields. In general, this method requires the passage of the network through an electrostatic field in a suitable chamber. The active ingredient, which is a fine particle, is introduced into the chamber through, for example, a strong wind stream, and is loaded onto the network while passing over the supplied roller. It is easy to see that this is a very simple method. However, the devices needed to achieve these results are well known in non-pharmaceuticals such as the manufacture of adhesives or adhesive paper.

To achieve a successful drug load, the network must be resistant enough to enable the loading of the genetic particles. Additives present in the reticular preparations that increase the electrical properties are as described above. In most cases it is necessary to coat the network with a substance to increase the adhesion of the powder before the electrostatic loading of the active ingredient powder. Examples of such materials include carboxymethyl cellulose, methyl cellulose and the like.

The material increasing the adhesion is added to the network in a conventional manner such as adding a solution dissolved in an evaporative solvent such as water and drying with hot air. Thereafter, to increase the adhesion of the active materials, the nets are coated with these materials and soon after coating or loading the active materials on-line. The adhesive then greatly enhances the binding of the active ingredient particles to the network. This is done to the network loaded by heat, pressure, moisture or a suitable mixing condition thereof.

In addition to the electrostatic loading of the powder cloud, the fine particle active ingredient is coated on the network in a dry state by the powder cogging method by electric gas power. In this method, the particles of active ingredient are exposed to the corona load and electrically charged and placed in an electrically insulated chamber parallel to the gas stream. The network passes through the anisotropy and is sent over the metal surface with the opposite polarity compared to the charged cloud of the active material date. The magnetic field between the particle and the metal surface attracts the active material to the network and loads it onto the network.

In addition, in the present invention, the active ingredient may be coated on the network in the form of a solution or suspension containing a fine drug such as a colloidal suspension.

The liquid used in such a process may be water, an organic solvent such as ethanol or an aqueous alcoholic solution. A preferred method of loading onto a moving network of active ingredients in liquid form is the electrostatic jet spray loading method. In this method, a solution or suspension containing the active ingredient is sent to a device capable of spraying microdroplets that are concentrated at a specific area of the network by using a limited electrostatic field. This method is good for loading small amounts of active ingredients such as hormones or enzymes into the network. A small amount means that the active substance has a dose of 1 mg or less.

In addition to the electrostatic jet spray loading method, a coating method that is understood in a different field from that used for coating a substrate with a liquid may also be used to load the active ingredient into the network. A paper network, for example, is passed under a roller immersed in a bath of saturated liquid. When the network passes through the rollers, excess liquid is removed from the network by other rollers, jetted air, rubber wiping bars, sticks such as coiled meyer rods, and the like. This is especially true when the solution penetrates the network, especially when the solvent used to liquefy or suspend the active ingredient is the same or similar to the solvent used to prepare the paper network.

While the object of the present invention is to load the active ingredient onto the surface of the network, penetration into the network is due to the application of heat and / or pressure to the network from the use of evaporative liquids for the active ingredient or to seal the network. Able to know. With these factors, such as evaporative liquids, one can simply experiment to calculate the percentage of active material loaded into the reticulated body. This instrument can thus be fitted to adjust the on-line test apparatus described herein. Once the required amount of active material has been absorbed into the network, it is necessary that the shell of the formulation be an unloaded, i.e. non-active, network in order to prevent the loss of titer breakdown of the active ingredient by exposure to air and moisture. Clear control of the assembly process, which will be described later, will achieve this result.

As mentioned above, one of the obvious forgetts of the formulations according to the invention is that the pharmaceutically active substances may be formulated in a stable formulation without mixing with the usual pharmaceutical excipients usually used in conventional solid formulations far exceeding the amount of active substance. Can be.

However, it will be appreciated that a small amount of inert material is required to load the active material into the network according to the present invention as described above. For example, when the active substance is to be loaded into the network in a dry state, a small amount, that is, about 0 to 10% (by weight) of the active ingredient, preferably about 1/4% to 2% of the glidant is mixed homogeneously, The purpose of this glidant is to improve the flowability of the powdered active material through the loading device. Suitable glidants include, for example, microparticles such as colloidal commercially available silica (trade name: Carb-0-Seal, manufactured by Carbot, Inc., Boston, MA), starch preparations such as talc, Flo, National Starch Co., Ltd.).

The inclusion and amount of glidants depend on the crystalline structure and the flowability of the active material. In some cases, preservatives may be mixed with the active substance, but this is usually not necessary when loading the active substance in a dry net. In addition, as mentioned above, in the scope of the present invention, the above-mentioned pressure-sensitive adhesive material is mixed with the active ingredient when loaded in a wet state, where the pressure-sensitive adhesive and the active ingredient are mixed with the same liquid carrier. In most cases, however, adhesives are used to increase adhesion when the active substance is added to the network. In any case, the adhesive material may be contained in an amount of 0 to 100% by weight based on the weight of the drug, preferably 0 to 30%.

The amount of active ingredient loaded onto the network according to the present invention can be varied depending on the formulation of the substance mentioned, the area of the network to be coated and the thickness of the coating. Additional factors affecting the amount of drug added to the network are the loading method, the type and sensitivity of the instrument and the on-line test device used during the assembly process described below. In all cases, however, the amount of active substance loaded on the network is such that it can contain a therapeutically effective dose in each unit dosage form when the loaded network is assembled and unitized. As an example of the latter determination conditions, evenly loaded drugs are analyzed by spectrophotometry using photon counting to measure the ultraviolet absorption of the active substance of the network, and the thickness of the active substance cannot exceed 0.005 cm. In any case, the amount of active substance loaded on the network is always expressed in mg or μg per cm 2 of the network. This is a decision for the entire network surface, although in most cases it is necessary to leave extra of the uncoated network used to seal the formulation.

The ability of the network to accept and internalize the active material according to the present invention is expressed as a network conversion factor (WCF) and is calculated by the following equation.

For example, when a network of 15.25 cm × 1.0 cm is exposed to a drug and assembled into a formulation of 0.5 cm × 1.0 cm, the network conversion factor is as follows.

The next step of the preparations according to the invention is the formulation or assembly step. As used herein, "assembly" refers to a network initially produced that converts into a solid geometry of a predetermined form that can be divided into a number of unit forms. This step proceeds through a continuous manufacturing process at high speed in connection with what is described above. This step converts the flat loaded network into a geometrical form and substantially embeds the active material in the protective coating of the network. The network thus formed is then finalized to unitize to a pharmaceutical unit dosage form suitable for oral administration. It should be noted that the preferred process is to allow the uniting process to proceed with or immediately after the assembly process.

There are various methods of granulation according to the present invention, which include tubular extrusion type, multilayer ribbon type, shelled rope type, dice type, and the like. The four main methods of making or assembling a network coated with the active substance are the pivoting method, the rotary method, the fan-folding method and the lamination method. These four important methods are described in detail below.

Before discussing in detail the manufacturing method for each invention, various criteria for acceptable methods should be reviewed again. The method of assembly or fabrication must be a high speed manufacturing process and be made of something with an accurate geometric shape with uniformity. The process should be practically inherent in the active substance. Finally, the assembly or fabrication process should not be excessively stressed to deform or tear the network, nor should it be a process of building a substantial amount of active material from the network. Each of the manufacturing processes described hereinafter will meet these criteria.

The first major method to be discussed is the method of rolling up moving meshes.

Perhaps there is a difference between the spiral winding and the spiral winding known in the paper industry, for example.

In the spiral winding method, paper is fed to a spiral winding machine from several rollers with coils having a width of 1/2 to 2 cm. A continuous piece of paper from each roller is wound like a coil, overlapping around a cylindrical mandrel supported at one end.

The adhesive applies to each piece of paper and the overlapping pieces so that these pieces are wound around the mandrel. The good paper thus produced is rotated around the mandrel by the action of a continuous belt that sends the unsupported end of the mandrel. At the end of the mandrel, the tube thus produced is cut to the desired length by the interruption of the high speed blade.

This paper always has a hole in the middle due to the mandrel. In the slewing method there is no mandrel, so it is not necessary to have a hole in the center of the formed rod. In fact, the present invention seeks to impose strict restrictions, in particular, on the removal of centrally formed holes.

Reference is made to FIG. 3, which shows one example of a method of winding in turns.

In the swirling winding process of FIG. 3, the coated or loaded reticular body 61 is supplied to a single roller through a device including, for example, a guide line 62 and a roller 63, and sent to a cutting device 64. Cut the reticular body horizontally to the desired length, usually 12 cm to 25 cm. Thereafter, the cut of the reticular body is sent to the crimping roller device 65 which pushes the reticular body into the soft rubber roller to be crimped.

As a result of the crimping action, the cut individual pieces of the reticular body are in the form of a loosely wound coil. The loosely wound reticle from the corrugated roller device is then passed between the fixed and moving surface, which gradually reduces the space between the two surfaces as the reticle passes. The stationary surface and the moving surface are fixed and the other one is a fixed plate 67 and a moving surface flattened in the form of two concentric cylinders which rotate relatively around the fixed cylinder or in the fixed surface state as shown in FIG. There is a form of the moving belt (66).

Loosely wound rod-shaped reticular cuts are passed between the moving surface and the stationary surface and tightly wound until a solid rod form is produced. By properly adjusting the width between the two surfaces, the rod-shaped one can be wound tightly without any holes in the middle. Of course, if necessary, the width of the gap can be adjusted to create a hole of a desired size in the middle of the manufactured rod-shaped one.

The rod form can be sealed by various methods. First, the conventional method used for producing confectionery cannot be applied in the present invention. In a conventional method, water is sprayed or coated onto a moving surface that is in contact with the network during the manufacture of rod-shaped ones to make contact with a large amount of the network. About 18% by weight of water absorbed in the reticular body is not only applicable to the preparation of the unit dosage form of the present invention because it not only damages the adhesive effect on the reticular body but also the drug itself. Moreover, the rod form produced by this conventional method is usually sealed so tightly that the state of drug release in the body is poor. After the preparation, the present invention is finely sprayed with a sufficient amount of water in the same amount of the network in the usual process, and then wetted and dried quickly. The final formulation is obtained with the stability of the active ingredient which is clear in terms of the proper mixing technique.

Secondly, the rods can be heat sealed to the wound edges of the nets of the reticular and sealed by adding edible polymers or heat sealed to the wound edges of the nets and coated immediately after cutting the long reticular with edible polymers. An optionally heat sealable polymer is added to the complete cut of the network by sheet or by constant coating. Suitable polymers are, for example, polyoxyethylene or cellulose ether ether derivatives which are soluble in water containing the plasticizers described above. Tightly wrap the rod into shape and seal it through the bottom of a hotplate that can apply both heat and pressure. For example, the fixed plate 67 may have a heated portion.

Optionally, the rod shape after manufacture can be sealed by adding water or pressure-sensitive adhesive to the outer layer or network. Water is preferred as a sealant. This method is required when a substance such as, for example, starch or starch derivative is in or on the network and then sealed by drying or by applying heat and pressure.

For example, the method described in FIG. 3 is suitably sealed in the form of a rod on the belt surface in contact with the reticular surface of the water sprayer 68 in contact with the outer surface of the long belt 66 along the lower return. It is enough to have enough water. Water may be applied to a tightly wound rod, for example, by passing the rod under a water transfer roller and uniformly applying the amount measured through the porous plate to the total length of the rod or by arranging the sponge on the outer surface of the rod. The rod form then passes between the stationary surface and the movement that allows for full sealing by applying pressure or pressure and heat.

This angle of sealing with water is clearly superior to known methods known in the art such as the confectionery described above, for example. When water is added as described above, the amount of water added to each rod type is less than that by the known method. As a result, the amount of water removed in the next drying process is substantially smaller than the amount required by the known method.

The rod-shaped one thus prepared is equal to the reticular width of the feed rate. Typical width is 20 to 40 cm. Each rod-shaped seal is sealed and then moved into contact with a very sharp blade 69 (FIG. 3) via a unifying belt 66, where the rod-shaped one is cut to the desired length. The method of making this rod form into the final formulation by the uniting and final step is described in more detail below.

A second production or assembly method that can be considered is a rotary type. This method can take many unique forms. This method can be considered a more general lamination method, in which the mass of reticulum loaded with active material in the form of elongate pieces or rods is initially produced by the fan-folding method of lamination described later. In one unusual rotary type shown in FIG. 4, a continuous, relatively thick laminated strip of the network 70 loaded with active material is passed between a pair of French rollers 71. This continuously manufactured or pressurized laminated mass 72 is sent to a second location, ie, to form and compact a rod, which consists of, for example, a stainless steel roller 73 with a circumferential edge and at least one spring. The strip is deformed into several continuous rods 74 or mostly to a circular or other desired cross section. This rod of the desired geometrical form (74) is then sent through the third round where there is a pair of suitable rollers suitable for uniting, for example, rod-shaped ones into individual formulations. to be. This is followed by an appropriate printing process and final finishing process. It should be noted that the printing process can be carried out in the uniting step containing the third roller set 75.

Another example of a rotary type is a long block (piece or rod) 81, as described in FIG. 5, with a die block 82 and / or a pair of die blocks at regular intervals. Reciprocating motion of the appropriate heated roller 83 will ultimately result in a rounded end unit formulation and release from where the formulation is made in a rotary fashion is a continuous chain of end unit 85 continuously connected. . Since all methods or various rotary methods according to the present invention are used, the modified rod form is allowed to pass through the printing and uniting process on the highway.

Another closely related rotary method feeds a continuous mass into a rotary form making and compacting device containing the aforementioned, such as one or more pairs of stainless steel rollers. The layer of the network consisting of a paper layer and a polymer film layer is heated and pressurized to form a continuous lump.

The outermost layer of agglomerates is preferably paper so that the agglomeration apparatus does not stick to the heated roller. During the compaction process, the reticular layers are joined together as units to reduce dislocations and dislocations of the layers during subsequent side and end manufacturing processes. The ends of the base formulation are then prepared by feeding the continuous right-angled mass produced in the dense place to the second place where the ends of the unit dosage form are formed by a pair of heated rollers having a cutter placed transverse to the roller face. The unit dosage form cut end is shaped and sealed with heat from the roller. The shape of the end cutter determines the end form of the formulation. The shape of the cleavage end face is designed to flexibly shift the side cleavage of the unit dosage form to be performed in the next step.

The sides of the unit dosage form are made end by lamination and the mass is cut into a heated third pair of rollers. This roller has an angular groove with a cutting blade. The shape of the groove of the roller face forms the cross section of the desired unit dosage form. The heat and pressure exerted from cutting the ridges on the rollers seals the sides of the unit dosage form to the smooth side.

Therefore, the rotary unit dosage form assembly method described in FIG. 5 is composed of three important places: a dense place, an end treatment place and a side treatment place.

Each site is preferably a heated set of rollers through which long reticular masses are passed. The shape of the outermost layer, that is, the shape of the roller face of each place, depends on the particular place and the result from it. Various additional processes, such as additional cutting, printing or final steps, can be performed at or between the three locations described above. This process will be described later in more detail.

It is within the scope of the present invention to include simultaneously performing one or more different processes in a rotary manner and in practice, for example, by inserting an endless long laminated strip through a pair of spring heated cooperating rollers, i. Form manufacturing process, formulation preparation process, uniting process and even printing process are all carried out at once.

The third exception rotary equation described above is an example of bringing two or more unit processes together.

This is accomplished by mixing the third rotary lamination press step and rod-shaped manufacturing step described above with the method also described in FIG. 4 using a pair of heating, pressurizing and cutting rollers (not specifically indicated), for example. And simultaneously pressurizing the laminate feed and cutting the ends to resemble the sides of a plurality of donuts stacked like a heap. This end cut surface is then fed into a unit formulator that is cut into lengths to allow for individual formulations.

For example, the printing step can also be performed at the latter location. The concept of the present invention includes the direct packaging of the unitized formulation, for example, as these formulations are put into blister strips by conventional devices and subjected to the uniting process.

The third method of preparing the formulations according to the invention is the pan-folding method. Again, the fan-folding method can be classified as a lamination method in a general sense. In this method the network, for example up to 30 cm wide, is initially assembled to contain the loaded active ingredient. This is done by first folding the mesh in half or laminating the two coated meshes with the coated sides on each other.

Initially, the reticular body is largely made up to 60 cm wide, laminated, divided into two or more by an area suitable for the fan-folding process, that is, divided into 1 cm to 15 cm, and then a pair of one or more reticulated laminations are united.

The coated network is initially folded or laminated as described above and then passed through a roll that is calibrated during manufacture for the pan-folding process. This gold engraved roll may or may not have power. The reticular body is basically moved by pulling the roll. Gold engraving can be done, for example, using a pair of gold-engraved rolls with springs. Since the reticle is preferably folded in the direction of the graduated ring marked on the reticle material, the graduated ring can be selectively positioned on the upper or lower rollers depending on the desired fan-fold style. The engraved reticular body is then sent to a fan-folding dropper with a folding surface that gently begins to bend the contact surface of the reticular body, compressing the area overlapping with the area, thereby densely folding the reticular body at the end.

At the end of the folding dropper there is a calibrator and a folding device, ie a device that pulls the reticular body through a pair of spring-loaded rollers made of stainless steel. This has the dual action, that is, the action of passing the network through the folding device and the function of compacting the folded network into a continuous solid geometry. Of course, within the scope of the present invention, it is also included to combine the attracting device with a device for sealing the network. However, the fan-folded network can also be sealed by other methods described later. The sealed network is then united in various ways such as the rotary type described above.

Figures 6a-d show a single fan-fold that initially stacks the fan-folded network 91 in a therapeutically inert network structure, preferably paper 92A in a hole in the central band 29. The formulation formulation has been described above. The center belt loaded with the fan-folded network is sandwiched between the outer bands 93 of the network to form a lamination structure. The subsequently laminated laminations are then supplied to a place such as a unit formulator, for example, by rotary type, or a unit 83 of figure 5 which has a strip shaped like the one shown in figure 6b.

Finally, or simultaneously with the process associated with FIG. 6B, a unitization process is performed to impart individual formulations as shown in FIG. 6C. FIG. 6d shows a cross section of the formulation shown in FIG. 6c. 6D shows how the fan-folded network 91 is fully internalized, for example, the center strip 92 is forced through a slightly outward forming process so that it is exposed between the edges of the sealed outer strip 93. Preferably, the outer band 93 and the center band 92 are free of active ingredients and are free of active ingredients on the outer surface of the individual formulation.

A fourth important manufacturing method that can be considered in accordance with the invention is the lamination method mentioned previously. In this method, the network is first unwound from about 20 to 60 times at the same time from several unwinding devices and then in the form of a long rod. The 20th to 60th layers of the reticular are all suitably coated paperlike materials that facilitate sealing in the next step, or are heat sealable with paperlike reticules, laminates or heat seals with edible polymers. It consists of a network of one or more papers sandwiched one by one over an edible polymer network. Suitable polymeric materials include, for example, polyoxy ethylene or cellulose ether ether derivatives which are soluble in water containing plasticizers. All of the reticular bodies are loaded with the active substance, and preferably the active substance is loaded with the paper reticulum.

An alternative method of stacking nets loaded with active material in piles is to feed the nets directly from the load device. Reticula usually 12 to 25 cm wide. The reticular bodies stored in the rollers or supplied from the load device are initially several times the final area that is cut to the desired final area as part of the stacking process.

Once the reticular piles are piled up, a series of lumps is sent to the lamination site. Apparatuses known in various techniques for sending together pieces of flexible film and forming laminates from them can also be applied and used generally in practicing the present invention. As already mentioned, the place where the active material is loaded onto the reticular pieces or plates can be changed, for example, according to the method of sealing the lamination. Cutting and final steps of the laminate can likewise be varied according to the invention.

For example, the laminate can be treated in the rotary manner described above. However, the lamination site is equipped with a pair of reciprocating die plates that constantly feed the network mass to form, seal and cut the formulation. A typical die plate has a surface of approximately 25 cm x 25 cm.

The laminate formed according to the invention was unique in that only the edge was sealed as opposed to being completely sealed to the adjacent plates.

It was found that exceptionally suitable formulations can be prepared from a mass of network layers sandwiching up to six sheets of paper between layers of polymer networks that can be heat sealed by applying a heat and pressure to the mass with a cutter during uniting. During the uniting process, the lumped layer of polymer network is deformed and spread by heat and pressure to cover and seal the edge of the layer between the paper compositions. It is readily understood that the top and bottom layers of such laminates should be of polymeric composition. The drug in the reticulated mass of paper polymer is preferably loaded into the paper layer of the reticulated body.

It can be readily seen from the above publication that the laminate sealed only at the distal end is far superior in the rate of drug release than the similar mass of the whole laminated network.

An alternative method of preparing the formulation from the network mass is to pass the mass between rotating cylinders with two individual dies at their outer ends. The unit dosage form continuously feeds the network mass between these rotating cylinders to produce, seal and cut the unit dosage form therefrom.

Some of the benefits of pharmaceutical compatibility can be obtained using the lamination methods described herein.

Firstly, the lamination method facilitates the mixing of two or more therapeutically active substances which are not pharmaceutically compatible without the use of special mixing methods such as adding stabilizers or filling one or more ingredients into capsules.

For example, since the lamination can be carried out up to 60 layers, this preparation of the present invention is ideally suited for pharmaceutically incompatible formulations. Furthermore, the insulating effect of the laminate layer and the loading of the active material to the network in a dry state are ideally suited for the preparation of foamed tablets.

Such formulations should be ones in which the network composition is readily soluble or dispersible in water.

In addition, as described above, loading the active ingredient into the network in a dry state is a useful method when the active material may adversely affect the moisture.

Furthermore, the lamination process of the present invention can not only change various layers to be laminated, but also adjust whether each is coated with the active ingredient. Clearly, the top and bottom surfaces that are exposed are uncoated and thus provide effective aging of the active material.

For example, sandwiching one or more starch layers between the cellulose layer may enhance plasticity more conveniently than increasing the amount of plasticizer in the cellulose layer formulation.

Regarding the above-described manufacturing method, in the present invention, it is preferable to load the active substance into the network in the wet form prepared by the turning method or the fan-folding method.

Rotary manufacturing and lamination processes can be used to load the active material in a wet or dry state depending on the nature of the active material being loaded, e.g. solubility in the specific solvent used, stability to moisture, and the like. have.

Indeed, referring to the unitization, one cannot but mention the sealing and also the first one to assemble. This is because the network formed by definition, cleavage, or unitization exposes the active material to one or more outermost layers. The exception to this is that, in contrast to the continuous loading method, there is a loading process that loads the active material at short intervals so that it is surrounded by an uncoated network with a “spot” active material. In light of the need to maintain the integrity of the load coating for the manufacturing equipment and on-line testing, it is desirable to load a sufficient amount of active material into the network continuously and to produce a unit dosage form containing a therapeutically effective amount through a uniting process. Do.

In processes such as the pan-folding formulations described herein, the reticular outer edges are free of actives to incorporate the actives therein and, in some cases, add excess reticular to enable the sealing of unit dosage forms.

The cleavage of the prepared network should be done in such a way that the network does not deform.

The cutting process itself may be by a fixed or rotary blade, a die with one or two ends, or by other conventional methods. Assembled reticular bodies can be transferred several times at different angles to avoid deformation during the cutting process. In addition, the reticular bodies produced in rotary manufacturing as described above may initially be slightly corrugated or twisted by a high speed unitization process.

The manufactured and loaded reticulum is divided into individual pieces, that is, cutting rod-shaped one piece at a time to produce one unit type. It is preferred to produce the units simultaneously. Another way to produce several unit dosage forms simultaneously is to cut a lamination reticulum, or a rolled rod-shaped one, using a die designed for either single or double rotary or reciprocating dies.

The shape of the final formulation is rectangular, square, preferably hexagonal, which fits the die plate in various shapes so that the cone shape is preferred and inevitably lossless.

The shape of the formulation prepared from the rod shape may be determined by the shape of the cutter. For example, the cutter may be in the form of a rectangular quadrilateral with moderately concave larger parallel faces such that the ends of the formulation are slightly rounded off. Many variations are readily apparent to those skilled in the art. However, it should be remembered that the side supports needed to prevent wrinkling and glare must be applied to the assembled formulation during the uniting process.

It is within the scope of the present invention to combine uniting and final finishing processes. Although there are many ways to seal the formulation, it is usually combined with the uniting process and carried out with heat and / or pressure. In addition to heating the cutting tool to seal off the separate edges of the formulation, heat and pressure can be applied through the die to seal the laminate. In addition, the use of moisture or volatile solvents to seal the edges of the spirally wound rods mentioned above can be extended to the cutting process by adding such solvents to the cutting surface. Heat and / or pressure may also be applied simultaneously to properly seal.

Methods for sealing unit dosage forms prepared according to the invention are conventional in the handling and lamination techniques of plastics. In addition to the use of water or ethanol methanol, or other volatile solvents such as chloroform, applying pressure and heat, applying pressure-sensitive adhesives, heating by ultraviolet light, ultrasonic bonding, filling or mixing of two or more substances into capsules are also included. Are contained. A preferred method of sealing the formulation within the scope of the present invention is to coat it with a preprinted one as needed. It is a thin layer of edible polymeric material such as, for example, hydroxymethylcellulose, modified starch, and is coated with the unit dosage form in a bath such that the unit dosage is submerged.

This layer may be self-sealed by methods such as volatile solvent removal. More preferred methods of coating the layer to be sealed on the unit dosage form according to the present invention are capsule filling and basket sealing.

First of these methods, the unit solid dosage form is passed between astringent layers of flexible films, such as gelatin containing the dosage form, for example, as detailed above in FIG. 6A.

The gelatin film is then heat sealed and cut into the desired shape. Capsule filling mechanisms of solutions by this method are known in the pharmaceutical art and such devices can be easily adapted for coating novel formulations according to the invention.

The second method is a basket sealing method performed by at least two processes. First, the basket is prepared from a material such as gelatin or cellulose derivatives by a device well known in the art such as a plastic mold, that is, an injection mold. The unit dosage form is automatically placed into this basket at high speed and then the basket is covered with an outer layer capable of sealing the basket by any of the sealing methods mentioned herein, preferably by ultrasonic methods. The basket is cut and branched with a classic or rotary cutting blade. Walls or prefabricated baskets are usually thicker than the top or sealing layers.

However, the sealing layer will be thick enough to protect the formulation so that it usually arrives in a very short time after administration of the formulation and will be released from the basket via the sealing layer in minutes. Optionally, the basket is made from the same shaped halves sealed by the method described herein.

An alternative method of sealing the basket described above may be a continuous feeding of the reticle for the basket and the holes formed therein or a strip of the material described above to produce an accurate formulation, such as a pan-folded formulation as detailed in Figure 6a. To supply. In this method the unit dosage form is placed in a hole, for example by a pin through the hole and a second pin on the top of the unit dosage form to keep under compression. The strip is then sealed by adding the top and bottom layers of similar materials while maintaining compression on the unit dosage form.

The thickness of the band is in no case thicker than the unit dosage form. However, the band is thinner than the formulation but not half the thickness of the formulation. The support strip is preferably for the same or about the same thickness of the formulation for several reasons. Firstly, the sealing film can be as thin as described above in connection with the basket since there is no significant twist during the sealing process. Second, thick support meshes are twisted during the drilling and uniting processes. Thirdly, the hole is closer to the thick strip, thus minimizing waste. Once the formulation is sealed by placing it on a support strip, the strip is again united as described above.

The advantage for both the basket and support strip described above is that there is a reticular material on the outermost surface that does not contain the active material and can be subjected to a final finishing step such as embossing, cutting at an angle without risk of losing the active material. The use of the concept of a basket or support strip also facilitates the use of changing the color of the final formulation, for example by making the contrast color of the support mesh, the seal of the strip or the unit dosage form itself, and thus the mood. This nice and clear appearance.

The material used for the manufacture of the basket, the central support strip and the sealing film described above shall conform to the basic acceptance test as for the reticular itself. In addition to clear pharmaceutical criteria such as purity, shelf life, non-toxicity, and compatibility with the active substance to be used, the substance must have good surface properties, accept color and ink, and be structurally complete, deformable, stable, and active in water. It must be to emit. Preferred materials for this use are hydroxy propylcellulose and methyl cellulose.

Particularly preferred compositions are those containing hydroxy propyl cellulose, starch or starch derivatives as weight and disintegrant, plasticizers such as polyethylene glycol, antioxidants such as titanium dioxide and BHT.

One of the important advantages of the novel formulations of the present invention is the ability to verify quality without collapsing on-line. In the present invention, the term "non-detructive" is contrary to the literal strict definition in practice. This means that quality verification of the new formulations according to the invention can be done during a high speed manufacturing process which is lost to less than 1% of the actual formulation.

Since the new formulations of the present invention are prepared with little difference from the standard value in terms of dosage, the amount currently lost during the test is actually a small amount in the actual pharmaceutical field and the amount lost in the overall manufacturing process since the current pharmaceutical field usually requires an excess of the standard value. Is close to “0”.

As a final formulation, the new formulations of the present invention can be quality checked during the manufacturing process, a unique concept in the pharmaceutical art. An on-line test procedure that allows for this identification is performed before the on-line test, which allows this identification of the components of the formulation prior to manufacture, such as chemical and physical control of the components of the formulation before manufacture begins. Examples of checks on the physical properties of solid dosage forms, including the control of chemical properties, the physical properties of dissolution rate, capping phenomenon, and chemical properties such as potency and incompatibility after completion of manufacturing For example, it is clearly distinguished from manual checks of two colored capsules to ensure that each end has a contrasting color.

These tests, which are used in the conventional pharmaceutical field and described herein, are neither independent nor can be done during the on-line manufacturing process that is characteristic of the solid dosage forms of the invention. However, conventional procedures such as, for example, strict quality control before the manufacturing process and testing for all active ingredients, can be considered for the complete manufacture of the formulation of the invention as in any good pharmaceutical preparation.

Quality verification by the on-line method during the manufacturing process of the novel formulations of the present invention is provided by the fact that such formulations described herein begin with a continuous edible network that is woven to test without disintegration. do.

Firstly, in the process of manufacturing the reticle itself, the physical properties of the reticular body are combined to check whether the reticular body is uniform and flawless. For example, a reticle can be constantly passed through a reticle through a resonant box that checks the reticular thickness. Once the number of resonances is obtained, the change in it represents a change in the reticular thickness. Other devices for checking network thickness include laser beam rotation, fluid detection and physical contact detectors. Moreover, according to this invention, it is also possible to test about the thickness and groove | channel of a network body per unit area.

A preferred method of testing the net weight per unit area is a soft X-ray absorption method, for example using a wavelength of about 4 GHz.

The β-ray absorption method using PM 147 can also be used. Reticular flaws such as smudges, holes and streaks can be detected by scanning the laser beam. Holes formed in the network can be detected by an electric charge method using a commercially available device.

The method detailed in the above can be equally applied to a second coating of the network with one or more of the networks or to a coating for protecting the loaded network.

Laser beam scanning is particularly useful for checking on-line the quality of such coatings.

A second important area for checking quality on-line according to the invention is to check the uniformity of the coating process as well as the amount of active substance added to the network. It should first be remembered that the clear advantage of the process by which the new formulations of the present invention are prepared is that the active material is loaded in the form of a microparticle or microfilm in the form capable of carrying out the test method described hereafter.

There are several ways to analyze the uniformity of active material loading. For example, a photon counter is used to measure the ultraviolet absorption of the active substance-reticle. Soft X-ray methods and β-ray absorption methods using wavelengths of about 4 GHz can also be used. Light scattering devices are preferred because they are ideally suited for checking particle size and concentration on powder clouds or reticular bodies. Suitable devices for this process are commercially available.

The assembly, uniting and final finishing steps described above can likewise be tested on-line as described above in connection with the network.

These tests are, of course, performed after assembly, and physical measurements such as size, thickness, and uniformity are performed on the network. Similar tests are also conducted for the unitary formulation in terms of shape, uniformity, and the like.

The focus of this technique is on an apparatus for testing the formulation of the invention on-line without collapsing during the manufacturing process. Within the scope of the present invention, two additional tests can be considered without departing from the concept of a "non-collapse test".

The first step in this process is to extract the fine parts of the network by periodically cutting them off-line with blades, dies, fluid jets or laser beams. It can be conceived that the small amount of extracted network does not destroy the entire network or adversely affect the assembly process. Reticulum samples are extracted either before or after loading of the active material, or in some early stages of assembly, for example when aggregating several reticules in preliminary lamination or folding. The sample thus extracted is chemically analyzed for both the reticular composition and the active substance. The assay also conducts quantitative tests, particularly for active substances.

In addition to spot analysis, final formulations can be sampled and checked on-line. Such testing is required for most solid formulation tests commercially available in the United States but is not performed on-line during the manufacturing process as is the case for the present invention. First, it should be remembered that the novel formulations of the present invention should not interfere with batches by the manufacturing process. Thus, “batch” according to the present invention may be the number of unit dosage forms placed between two samples consistent with the test specification without exceeding the number required for sampling in the Federal Food and Drug Administration (FDA). Since the sampling process contemplated by the present invention substantially exceeds these requirements, the “batch” for the new unit dosage forms as claimed herein is a convenient number such as the number of unit dosage forms that can be prepared from a given active substance. Can be.

A second unique aspect of the functional identification test of the formulations of the present invention is that all of the on-line tests described herein, as well as the results of these tests, can be computerized and the instrument can be controlled and used during the manufacturing process. Thus, if a test shows a negative, it means that the unit dosage form to be separated begins to run short, and the result of being positive again after correction is not automatically run out. The unit dosage form produced between these two tests shall then be tested to see how compatible with the specification.

If the test is performed on-line, for example, on the amount of active substance loaded on the network, the negative value will automatically record two actions at the same time. First, the reticular can have a point of non-toxic dye, which can temporarily stop the manufacturing process and extract a part of the reticular by hand. Secondly, the readings from the computer can tell if the amount of active substance loaded into the network is greater or less than the specification, and can be adjusted appropriately.

When the network passed the test device again meets the specification, the second point will automatically appear on the network to indicate the length of the network that does not match the specification. Similar processes are performed at each stage of the on-line test.

For the action analysis process, the final unit formulation is optionally sampled and automatically added to some test solution to test the dissolution rate. The particular criteria used to test the dissolution of the unit dosage form will vary depending on the active substance or the substance contained in the formulation.

For example, the sampled unit dosage form can be added to a suitable solvent to prepare a solution of the active ingredient. The resulting test solution can be optically injected to measure the concentration of active ingredient as a function of time after the unit dosage form has been added to the solution. Other possible indications that can be measured in the test solution are changes in pH, color, heat and chemical reactions. Devices that can automatically record each of these changes as a function of time are well known to the technicians. Once the information on the dissolution has been recorded, it can be used by machines such as computers to correct them in manufacturing, uniting, final finishing and sealing processes.

The on-line test method described herein can be used in all cases to test a complete network, such as a device for testing network thickness. In some cases, however, testing of complete reticular forms may be impossible economically. For example, light scattering detection can be used to test small areas of the reticular body, and it can also be closely mounted to two or more detectors to scan a narrow number of categories within the reticular body. However, the cost of the device needed to inject the entire network can be avoided.

Therefore, when only a limited area of the reticular body can be examined, the test device can be fixed on the device to facilitate vibration across the reticle area. The percentage of reticular and final unit formulations tested by this method far surpasses any non-degradable test methodology practiced in the field of conventional pharmaceuticals.

As has been discussed in various respects herein, the final finishing process of the novel formulations of the invention can be carried out on its own or preferably in combination with other processes such as unitization.

The final step in the new formulation of the present invention can be divided into two basic ideas: the uniformity of the surface of the body shape, the surface finish or appearance.

The uniformity of the surface of the formulation of the present invention may or may not be a problem depending on the method used to unitize the formulation into long continuous masses and whether it has been sealed. For example, when the laminated reticulated mass is cut into the special shape described above, it is obvious that there is a small glare to encounter the cutting device. There may also be terminal or side scintillation during the uniting process in formulations made by other preferred assembly methods as well.

In general, however, the assembly method according to the invention minimizes the manifestation of such flashes.

The flashes described above can generally be removed by mild abrasive phenomena such as mildly vortexing the unit dosage form with or without a mild abrasive such as, for example, salt crystals. This action usually has to precede the printing process. The surface appearance, ie the gloss of the formulation of the present invention, can vary from a soft pale yellow appearance to a very high gloss depending on the desired uniting and the method of the final finishing process. Using sealing methods such as the above mentioned basket sealing or capsule filling method, the gloss of the surface of the final formulation can be adjusted as desired by simply selecting the material used to form the seal. It is equally true to seal the formulation using the shell. This sealing process generally eliminates the need to completely remove the glare because the sheath is completely uniform.

The printing process likewise depends on the assembly process and sealing method used. The printing process may be performed on the network itself at a convenient point in the overall manufacturing process.

For example, the outermost layer of the laminated formulation can be printed before the assembly process or after completion of the uniting process as part of the uniting process. Formulations prepared by rolling up may also be printed in the form of long rods or lumps. When the formulation of the invention is encapsulated and encapsulated, the printing is preferably printed after enveloping, although within the scope of the invention it can be printed on the formulation and then enveloped. Printing solid unit formulations prior to complete mixing as described herein is a unique concept in the pharmaceutical art.

The choice of printing method depends on several factors, the most important physical properties of the substrate to be printed. Likewise, the selection of a suitable method is carried out at the point where the printing process is carried out in the whole process, i.e. printing on the reticulum prior to assembly, printing on the final formulation, or in combination with other processes such as the intermediate point, ie the uniting process. It is somewhat relative in that respect. Printing methods and devices corresponding thereto include offset and direct printing, offset gravure, slabs, electrostatic powder gravure, electrostatic screen printing, and ink jetting. Of course, offset gravure can be used in other cases in special cases and is the best method even if the technical new printing method described herein can be conceived within the scope of the present invention.

The color of the formulation of the present invention can easily be combined from the final finishing process and the printing process described above that there are many ways to change the color in both hue and intensity. Firstly, the reticular composition itself may be colored in which several layers may combine to darken during various assembly processes. The color may also be put in a shell or seal layer. When using a basket seal or capsule filling method for sealing, two or more contrasting colors are possible by a clear method of changing the color of the various sites. Formulations prepared by lamination may be changed only by changing the color of the network fed to the lamination device. Other variations of this method are readily apparent to those skilled in the art.

Indeed, the novel formulations of the present invention are not limited to the type of active substance that can be used as the carrier.

The terms "active substance", "active ingredient" and "drug" have the same meaning in the present invention and can be used interchangeably in the description and claims, and are defined as substances that cause pharmacological reactions in the body. Can be. These materials include but are not limited to:

Benzodiazepines, such as chlorodiazepoxide, diazepam, flulazepam, oxazepam, chlorozephate, and the like, compounds which may be further added under the heading “benzodiazepines” are described in the following references and are not limited thereto; [See: Garattim, Mussini and Randal “The Benzodiazepines” Leiven Edition, 1973]

Other mental stabilizers such as reserpin, thiopropazate and phenothiazine compounds such as perphenazine, chloroproazine and the like; Stabilizers and hypnotics such as phenobarbital, methylprilon glutetimide, ethchlorbinol, metaquaarone and the like;

Psychoactive agents such as amitriptyline, imipramine, methylphenidate and the like;

Narcotic and non-narcotic analgesics such as codeine, levorpanol, morphine, propoxyphene, pentazocin and the like;

Analgesics such as aspirin, phenacetin, salicyamide, etc .;

Anti-inflammatory agents such as hydrocortisone, dexamethasone, prednisolone, indomethacin, phenyl butazone and the like;

Antifungal / sympathetic blockers such as atropine, papaverine, propaneterin, dicyclomine, corindinium, and the like;

Antihistamine / antiallergic agents such as diphenhydramine, chlorpheniramine, tripelinamine, brompheniramine, etc .;

Decongestants such as phenylephrine, pseudoephedrine and the like;

Diuretics such as chloro taziazide, hydrochlorothiazide, flumetiazide, triamterene, spironolactone and the like;

Nutritional substances such as vitamins and essential amino acids;

Parkinson's disease therapies alone or in combination with agonists such as N'-DL-seryl-N ^2- (2,3,4-trihydroxybenzyl) hydrazine;

Androgenic steroids such as methyltestosterone and fluoxymesterone;

Progesterone preparations such as progesterone, ethysterone, noethinodrel, noethine drone, methoxyprogesterone and the like;

Estrogen substances such as estrone, ethynyl estradiol, diethyl steel, and the like;

Hormonal agents such as prostaglandins, ACTH and the like;

Penicillin, cephalosporins, tetracyclines, chloro tetracyclines, streptomycin, erythromycin, sulfonamides, such as sulfisoxazoles, sulfadimethoxins, sulfamethoxazoles, and other agents, such as nitropurazone metronidazole, etc. Antibiotics / anti-infectives;

Cardiovascular preparations such as nitroglycerin pentaerythritol tetranitrate, isosorbide dinitrate, digitalis preparations such as digoxin and the like;

Antacid / anti-air blowing agents such as aluminum hydroxide, magnesium carbonate, simethicone and the like;

Therapeutic and / or admixtures for use in the therapeutically useful pharmaceutical field.

The active substance used in the present invention may be in free form or in pharmaceutically nontoxic form with still therapeutic effect. For example, the acidic material may be an salt with an ethrel or an inorganic base such as pharmaceutically harmless sodium, salt, potassium salt or an organic base in amine or quaternary form. The basic substance may be a salt with an organic acid such as acetate or tartrate. Substances such as ampicillin may be hydrated. In general, pharmaceutically acceptable forms of the active substance known in the pharmaceutical preparation process can be used in the formulation of the present invention, of course, it is excluded that is incompatible with the network substrate. In some cases that are incompatible, they can easily be identified by simple experiments.

The mixed amount of the active substance or the substance used in the mixing of the new formulation of the present invention is usually a therapeutically useful dose for a particular drug. In general, the amount of active ingredient in one formulation should have a practical upper limit of 750 mg, but not more than about 500 mg.

As mentioned, the novel formulations of the present invention have a very constant release rate that may be adjusted to conform to the desired specifications. Therefore, in any release form, the formulations of the present invention have a constant release rate in a form that is much better than that seen in solid dosage forms such as conventional tablets and capsules.

Figure 7 shows the superiority in the release rate of the formulation of the present invention compared to conventional oral solid formulations, ie commercial capsules. The experiment detailed in FIG. 7 puts six randomly sampled capsules containing six equal amounts of active substance into 100 ml of artificial gastric juice (according to USP, no enzyme), respectively. The solution is stirred at 37 ° C. The solution in each reaction flask is filtered without boiling to reflux in a cell in a suitable spectrophotometer.

The absorbance of the solution is read at intervals of one minute and the percentage of active ingredient dissolved is calculated from this figure. 7 shows the fastest melting and the slowest melting in each group, with the shovel-shaped area between them for the remaining four samples. Looking at Figure 7, we can easily make two decisions. First, the novel formulations of the present invention dissolve faster than conventional tested capsules. Second, the difference between the six samples in the unit dosage form of the present invention is surprisingly small than that of the conventional capsules tested. These results show that the formulation of the present invention is characterized by a much better constant release.

The blood concentration curve described in FIG. 8 also compares the commercially available capsules containing the same amount of the same active ingredient with the novel formulations of the present invention. Blood concentration curves are theoretically pharmacodynamically plotted based on the rates for the two formulations. Blood concentration curves are plotted based on theoretical 100% uptake of the amount of active ingredient released at any point as release over time of the formulation and is proportional to the rate of dissolution. Therefore, the difference in blood concentration curve is a function of the rate of dissolution. As seen in FIG. 8, the formulation of the present invention clearly establishes that not only effective blood levels are faster than conventional capsules but also higher blood levels of active ingredients. The ability to obtain higher blood levels of active ingredients sooner is a particularly clear advantage in terms of the administration of chemotherapeutic agents such as antibiotics, cardiovascular agents and the like.

Claims (1)

Reticulum formulations are prepared by loading the medicament into a therapeutically inert and edible reticulum and assembling it into a solid geometric formulation of a predetermined form, then uniting it into a number of unit dosage forms and sealing the unit dosage form so that the medicament can be fully embedded. How to.

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