Solid pharmaceutical form programmable selection for oral administration and its preparation

 

(57) Abstract:

The invention relates to medicine. The essence of the invention: solid pharmaceutical form programmable selection, representing the core containing the active ingredient and coated with a layer containing a hydrophobic material with a melting point of 50 to 90 C, surface-active substance with a value of HB 10 - 16.

The invention relates to a solid pharmaceutical dosage form intended for oral administration, in particular for use inside a solid pharmaceutical dosage form, the selection of medications from which begins after a predetermined period of time after its introduction.

Such dosage forms will hereinafter be referred to as the "dosage forms with programmable selection, thereby characterizing solid pharmaceutical dosage forms that release the active ingredient after a predetermined (programmed) time interval (interval without discharge) since the introduction of the form, as opposed dosage forms for immediate discharge, which releases the active ingredient is almost completely in the moment of introduction, and gradually, since inception.

Pharmaceutical dosage forms of programmed selection can be used to treat various pathologies.

It is known that the treatment of many pathologies requires a high concentration of drug in the blood for a limited period of time, and preferably in due time.

As examples can be mentioned the treatment of pathological conditions associated with the biological processes that are subject to external rhythms, such as regulation of blood pressure, excretion of hormones and chronobiology of asthma. An example is the treatment of myocardial infarction and other heart disease.

Known methods of treatment, including the use of rapidly destroyed in the metabolism of drugs, or drugs acting on receptors, which are inactivated by prolonged drug interactions (tolerantnosti).

For such methods of treatment, dosage forms for immediate allocation inconvenient because you have to enter them several times a day, whereas the use of dosage forms for the controlled allocation is not possible to obtain the desired therapeutic concentration. So obrazuemoy activities asthma and antitussives, allow to optimize the beneficial effect of the drug by reducing side effects.

In addition, a suitable delay interval selection can be a means of ensuring the "site-specific" selection in a specific region of the gastrointestinal tract, for example in the colon.

This is particularly valuable for the treatment of diseases of the colon, such as local infection, local spasms, tumors, ulcerative colitis and disease Chrona.

Moreover, the colon represents the best allocation of some somatically active drugs.

It is known that the secretion in the colon some somatically existing drugs is a valuable solution somatic absorption of drugs that cannot be administered orally because of their sensitivity to the effects of digestive enzymes.

Specific examples of drugs that are sensitive to the action of digestive enzymes, are peptides and proteins, such as insulin, gastrin, pentagastrin, calcitonin, glucagon, growth hormone, corticotropin, enkephalin, oxytocin, parathyroid g is only by pharmaceutical forms as suppositories. However, these pharmaceutical forms are not always able to ensure the efficient allocation in the colon.

Known oral pharmaceutical form in which the core containing the active ingredient, coated with an anionic polymer soluble at pH above 5.5, and water-insoluble layer.

This pharmaceutical form, however, cannot provide effective selection inside the colon due to the fact that the release of active ingredient, depending on the pH, can only begin 1-2 hours after dosing.

Also known solid oral form with coverage of the anionic polymer that is not soluble when passing through the upper part of the gastrointestinal tract. However, to ensure the integrity of the solid oral form before entering it into the colon requires a large amount of anionic polymer. The selection of this dosage form is also dependent on pH.

Known multi-layered tablet provides a selection of the medication through a certain period of time and in particular in the colon. Such pharmaceutical dosage form consists of a nucleus and the outer shell.

The shell consists of an inner layer of anion is the outer layer, representing ustoichivy in the environment of the stomach polymer.

The disadvantage of this tablet is also dependent on pH.

Since pH varies along the gastrointestinal tract within physiologically normal values, dependent on the pH of the pharmaceutical dosage form does not necessarily guarantee an efficient allocation of medication at a specified time and at the specified location.

In addition to the described pH dependent pharmaceutical dosage forms, we investigated a different approach, providing a selection of drugs in the intestine, which is used to cover the material, sensitive to enzymatic degradation.

And with this approach, the selection of drugs also depends on physiological factors, which may vary from individual to individual.

Known multi-layer tablets containing the active ingredient in a mixture with superdisintegrants.

Each tablet fully Partita (except for one plane) impermeable substance, while the free plane Partita layer of gelling and/or permeable material.

Superdisintegrants swells due to cutting the Wu.

There is extreme difficulty industrial implementation of the production of such pharmaceutical dosage forms that require special care during the election coverage of all surfaces of the tablet, except for one, impermeable substance, and then at the floor free plane water-permeable materials.

Also known pharmaceutical dosage form, which are areas in which contains an inert core, such as diabetes Tronic covered drug, then covered with disintegrants and outside coated with water-soluble and permeable material.

A spherical particle with a diameter of about 1 mm, allocate medicine after the expiry of a certain period of time, depending on the thickness of the outer coating, due to the rupture of this membrane due to swelling of disintegrant, which is the intermediate layer of the shell. However, many drugs cannot be applied in the form of a film on the core, making such pharmaceutical dosage form is not always acceptable.

From a technological point of view especially difficult is the provision of a uniform thickness water insoluble outer layer abolone such dosage forms is a mixture of small spherical particles with an external coating of different thickness of the water-insoluble material, that provides controlled selection.

The aim of the invention is the creation of a solid pharmaceutical dosage forms for oral administration, the selection of drugs which occurs after a specified period of time after its introduction, the creation of a solid pharmaceutical dosage forms for oral administration, which releases the drug over a specified period of time and which can easily be obtained on an industrial scale using available usually industrial equipment and standard techniques, creating a solid pharmaceutical dosage forms for oral administration, highlighting the medication after a specified period of time, the duration of which does not depend on the pH of the gastrointestinal tract, as well as creating a solid pharmaceutical dosage forms for oral administration, allocating the medicine after a specified period of time, the minimum duration of which varies from individual to individual, and creating a solid pharmaceutical dosage form for oral administration, suitable for the selection of drugs in the colon.

The goal of the invention PR is a preparation for oral administration of the coating layer, representing a mixture of a hydrophobic material and a surface-active additives and optional material, forming a water-soluble film.

Thus, the purpose of this invention is a solid pharmaceutical dosage form for oral administration with the programmed selection, representing the core, suitable for oral administration containing an active ingredient coated with a layer composed of a mixture of hydrophobic material with a melting point between 50 and 90aboutWith surface-active substances, the value of HB which varies between 10 and 16, and the amount of surfactant is from 5 to 20 wt. % by weight of hydrophobic material, and optionally, the material forming the water-soluble film, taken in an amount of 5-30% by weight of hydrophobic material.

To simplify the layer representing according to this invention, a mixture of a hydrophobic material with a surface-active substance, and optionally, forming a film of a water-soluble material called "hydrophobic layer.

Of dosage forms programmable selection of the drug released after a certain length of the t on pH, as well as the motility of the gastrointestinal tract.

At the end of this time interval begins with the selection of medicines, the kinetics of which depends on the type of pharmaceutical preparation, which consists of the core of the dosage form.

After a predetermined interval of time, the drug released or quickly if this drug is an immediate highlight, or slowly if the kernel is a controlled drug selection. The second option is useful in particular in the case of drugs designed specifically to treat colon.

Thus, the core of the dosage form, which is the aim of the invention is a solid pharmaceutical preparation for oral administration, in particular tablets or capsules immediate or controlled allocation.

Hydrophobic material forming the hydrophobic layer is a grease or other hydrophobic substances, the melting point of which is between 50 and 90aboutC.

Examples of hydrophobic materials that can be used in this invention are esters of higher fatty acids with higher alcohols, higher alcohols, higher fatty acids of two or more of the listed substances.

As specific examples Carnauba wax, beeswax, cetyl alcohol, stearyl alcohol, paraffin wax, microcrystalline wax or wax oil bitumen, stearic acid, myristic acid, hydrogenated castor oil, solid fats, and mixtures of two or more of the listed substances.

In a preferred embodiment, the surfactant comprising a hydrophobic layer is selected from non-ionic surfactants or mixtures thereof.

As surface-active additives can be used esters of fatty polyatomic acids with sorbitane and fatty ethoxy-alcohols.

The amount of surfactants ranges from 5 to 20 wt. % (based on hydrophobic material and preferably is approximately 10 wt. % .

Examples of substances which can be used according to this invention, to create a hydrophobic layer is a mixture of mono-, di - and triglycerides and diesters of polyethylene glycol.

The presence in the hydrophobic layer of water-soluble film-forming material is optional, since its principal function is to ensure the adhesion gids promote adhesion, what is 5-30 wt. % (based on hydrophobic material, preferably about 15-20 wt. % .

For purely practical reasons it is preferable to use water-soluble film-forming material.

Examples of water-soluble film-forming materials are hydroxyethylcellulose, esters, polymethacrylic acid and polyvinylpyrrolidone.

It should be noted that all components of the hydrophobic layer according to this invention, are well known and pharmaceutically acceptable materials, most of which has already been made, what is the advantage of the proposed dosage forms.

In this regard, it should be noted that although these materials are well known in pharmaceutical technology, they were used in different ratios and for other purposes, in comparison with this invention.

It is known, for example, the use of hydrophobic materials such as waxes, also in a mixture with surface-active agent or film-forming material to obtain a dosage form of the controlled allocation to obtain soluble enteric coatings.

Pharmaceutical dosage forms, which are the subject tandoori.

In practice, there may be used any medication, physical and chemical characteristics which are suitable for the preparation of solid pharmaceutical forms such as tablets and capsules.

Examples of drugs that the proposed dosage form according to therapeutic advantage in the treatment of these pathological conditions: anti-hypertensive, anti-asthma remedies, antitussive, anti-allergic, anti-inflammatory, protivopodagricakih, Antirheumatic agents, means, as a cardiac tonic, antispasmodic, hypnotics, sedatives, analgesics, anticancer and antibacterial drugs, proteins and hormones, and drugs used in veterinary medicine.

Specific examples are kromolin, acetylcysteine, dropropizine, ibuprofen, diclofena, naproxen, aspirin, netorola, mesalamine, indomethacin, sulfasalazine, diltiazem, ibopamine, isosorbide mono and dinitrate treatment, nitroglycerin, propranolol, oxprenololi, alprenolol, cimetropium bromide, insulin, gastrin, pentagastrin, calcitonin, glucagon, growth hormone, ACTH, andorfine, oxytocin, parathyroid hormone, vasopressin, cortisol, corticosterone, alprazolam, trazolam, oxazepam and by ekjcvw may be in the form of salts of the pharmacist optically active forms.

The manufacture of dosage forms according to this invention is carried out according to known methods using standard equipment. At the core, which contains the active ingredient is applied in the form of a film suspension (in water or an organic solvent) of hydrophobic material, a surfactant and, optionally, water-soluble film-forming material.

The coating is applied in accordance with the traditional methods of creating a film coating.

The core is a pharmaceutical composition for immediate or controlled allocation consisting of the active ingredient in a mixture with suitable excipients.

If necessary, the core may be protected by a water-soluble film, and then coated hydrophobic layer.

Using pharmaceutical dosage forms, which are the subject of this invention, it is possible to program the delay interval selection by choosing the appropriate thickness of the hydrophobic layer and equal to the thickness due to the choice of the type of hydrophobic material. It is obvious that the thickness of the hydrophobic layer is determined by its mass.

Hydrophobic materials with more n the tion delay interval selection.

On the contrary, the content of the surfactant in the hydrophobic layer, in a specified mass range that did not have a significant impact on the duration of the delay interval of the selection.

In the same way you can program the place and also the selection of drugs.

In practice, in cases where put in order the release of active ingredient over a certain period of time after the drug is preferable regardless of where there is a selection of medicines, the use of dosage forms consisting of a core and a hydrophobic layer.

In this case, it may be useful, depending on the dose of injected drug combination dosage forms for immediate discharge from the dosage form programmable selection offered by this invention which provides an introduction for one of two doses of the active ingredient released at different times.

This option can also be used for the simultaneous introduction of at once in two different active ingredients, active at different times.

This can be achieved by simultaneous administration, for example in this invention.

The same result can be achieved by alternative - drawing on dosage form programmable selection according to this invention the outer layer of immediate discharge, which contains the same or a different active ingredient.

In cases where the goal is the selection of medicines in a specific location, such as in the colon, when selecting the appropriate hydrophobic layer has to consider the time required to complete the form through the stomach and through the small intestine.

However, the time of passage through the stomach may vary within wide limits, from minutes to several hours, mainly depending on, is it the food or not.

It does not matter if the aim is to highlight the medication through a certain period of time that the drug was released in the colon.

Therefore, in the second case, the dosage form should be entered between meals or after taking light food.

Alternatively, when applied to the metered formu soluble in the intestine, or interoperate, coatings, i.e. stable in the stomach poires small intestine, and the delay interval allocation does not depend on the time of passage through the stomach. The application of the enteric coating is carried out by traditional methods using enteric polymers (interpolymers) in an organic or aqueous solvent.

For enteric coatings are suitable, for example, phthalate of acetylcellulose, copolymers of methacrylic acid with esters of methacrylic acid, the phthalate of hydroxypropylmethylcellulose, terephthalate of acetylcellulose.

To the listed polymers can be added that is not required, suitable plasticizers, such as, for example, polyethylene glycol, dibutyl phthalate, diethylphthalate, triacetin, castor oil, citrate.

In addition, to improve the characteristics of the final product in enteric film can be added talc or other fillers, as well as, but not necessarily, dyes approved for pharmaceutical use.

Almost the pharmaceutical dosage form according to this invention is implemented as:

tablets consisting of a nucleus immediate selection, which contains the active ingredient, patriliny ingredient, covered with a hydrophobic layer;

tablets consisting of a nucleus immediate selection, which contains the active ingredient coated with a hydrophobic layer;

tablets consisting of a nucleus immediate selection, which contains the active ingredient coated with a hydrophobic layer and covered with additional outer layer immediate selection, which contains the same active ingredient;

capsules containing the active ingredient and coated with a hydrophobic layer;

capsules containing the active ingredient coated with a hydrophobic layer and outer enteric coating;

capsules containing tablet immediate allocation and tablet programmable selection;

tablets consisting of a nucleus immediate selection, which contains the active ingredient coated with a hydrophobic layer and outer dissolving in the intestines coating;

tablet consisting of a core of a controlled allocation, which contains the active ingredient coated with a hydrophobic layer and outer dissolving in the intestines coating.

Due to the fact that the selection of drugs after a specified period of time not dependent on pH and on and the ical reactions.

In the manner of a working hypothesis, the observed effect can be explained by physical interaction dosage forms with body fluids, which leads to a slow and uniform dispersion of a hydrophobic layer, until undamaged (intact) the engine will not be in contact with body fluids, resulting in the medicine is released.

Due to the fact that the mechanism of delayed allocation is still not clear, a priori prediction of the exact duration of the delay period selection can be difficult.

It appears, however, that the desired delay interval allocation is a direct function of the thickness (i.e., mass) of a hydrophobic layer (see example 18), and to a lesser extent, depends on other parameters, in particular the melting temperature of the hydrophobic material.

There is very good correlation between the results of the simple and affordable test for the in vitro selection and allocation observed in vivo.

The in vitro tests described in detail in example 1, show that the observed delay interval selection (in vitro) corresponds to the average value of the delay interval selection observed in humans (see examples 2 and 3), with very Khoroshevskaya to select options, providing a desired length of delay interval selection, and a simple test in vitro confirms the expected result or indicates a need to change the selected parameters within the limits proposed by this invention.

Dosed pharmaceutical form, which is the subject of this invention, has as compared with known forms of advantages.

Firstly, programmable selection of drugs makes pharmaceutical dosage form, which is the subject of this invention is convenient for the introduction of the different medications used in the treatment of pathological conditions, subject to biological rhythm, because it optimizes the beneficial effects and reduce the side effects of their use.

Programmable selection of medicines in specific areas of the gastrointestinal tract, especially the colon, allows the use of the pharmaceutical dosage form, which is the subject of this invention, for injecting some drugs, when selecting which in another place a positive therapeutic effect reduces or have adverse effects.

Such dosage Pharm the ptx2">

The duration of the delay interval allocation does not depend on the pH of the gastrointestinal tract, as well as other physiological parameters. This advantage is evident in comparison with the known compositions intended for the same purpose, you can also use a dosage form according to this invention for the treatment of patients with pH in the gastrointestinal tract does not correspond to the normal, for example for the treatment of patients suffering from Floridia or taking medication to reduce the acidity (antacids drugs or H2-antagonists).

The examples do not limit the scope of the present invention and are for purposes of illustration.

P R I m e R 1. A General method.

Preparative methods.

The manufacturer of the engines which caused the hydrophobic layer was performed using conventional excipients and traditional preparative methods.

On the thus obtained core caused by known methods of creating a film coating (fluidized bed or bath for coating) layer previously prepared suspension containing a hydrophobic material, surface-active additives and neobyazatelnoe hydrophobic material with a surface-active additive at a temperature of 80-90aboutWith, after which were added small portions of boiling water, with appropriate stirring and, last but not least, the mixture was cooled to room temperature.

In those cases, when you enter the water-soluble film-forming material to the suspension add water its solution prepared by adding a water-soluble film-forming material to the boiling water with stirring and then cooled to room temperature. The resulting suspension is filtered (180 mesh), then applied as a film coating on the core and dried in a current of air.

Before applying the film coating of the core can be protected with a water-soluble film.

The result of the pharmaceutical dosage form can be applied additionally external cover, which are soluble in the intestine layer.

Applying soluble in the intestine of the coating can be, for example, by diluting a commercially available aqueous slurry and applying it on the dosage form according to this invention using conventional methods of creating a film coating (fluidized bed or a bath for coating).

In addition to specifically what Ales the following excipients:

Polyvinylpyrrolidone: material produced by the BASF Company under the trademark Kollidon K 30"

Crosspovidone: used polyvinylpyrrolidone, produced by the BASF Company under the trademark Kollidon CL

Colloidal silica: used material produced by Degussa Company under the trademark "Aerosil 200".

Surface-active additive: used Polysorbate 80, produced by ICI Americas Company under the trademark "Tween 80" (HL 13 151).

Enteric polymer (interpolymer):

Copolymer of methacrylic acid with methacrylic acid, produced by Rohm Phar. Company under the trademark "Endragit L30D"

PEG 6000: polyethylene glycol 6000.

The hypromellose: for water-soluble films used hypromellose viscosity of 5 CPS, for hydrophobic layer is used the viscosity hypromellose 15 CP.

Assessment allocation in titro.

The release of active ingredient in vitro was determined by the method of dissolution.

Evaluation of in vitro was carried out in Apparatus 2 at 100 rpm To confirm these data, the same test was carried out at 50 rpm, in water, in an environment that simulates the environment of the stomach: in the buffer with a pH of 1.2; in buffer with pH 5.5, buffer is a time delay selection on pH.

Evaluation of selection in vivo.

The release of active ingredient in vivo was determined using gamma scintigraphy.

To estimate the time and space allocation in the core was introduced as a component of samarium oxide. Irradiated pharmaceutical dosage forms, and then the labeled dosage form was administered to a healthy volunteer.

Gamma radiation was detected by a gamma camera.

Correlation of data in vivo and in vitro.

Comparison of data obtained in vivo and in vitro shows that between them there is a linear correlation.

In particular, certain in vitro latency interval selection testing 3.3% aqueous solution of sodium chloride has basically the same magnitude as that observed in vivo latency interval selection, whereas when tested in vitro in the water the obtained value amounting to half of that observed in vivo.

P R I m m e R 2. Preparation of labeled tablets to assess exposure in vivo and in vitro.

Cores were prepared by traditional methods of pressing, and each conform to the following composition: Dye E110 3.0 mg

The samarium oxide (enriched 152 Sm) 2.0 mg Lactose 77,5 mg Corn edges of the coating in the form of water-soluble protective film, having the following composition:

Hydroxypropylmethyl - cellulose 0.75 mg RE 6000 0.08 mg

Next on the core with a protective coating caused hydrophobic layer, prepared and applied in accordance with example 1, the following composition: Carnauba wax and 32.3 mg beeswax to 13.8 mg of the Surface-active additive of 4.6 mg Hydroxypropylmethyl - cellulose 9,2 mg

Evaluation of in vitro selection.

Evaluation of in vitro selection was performed according to the method of dissolution according to example 1.

The tests were carried out using a 3.3% aqueous solution of sodium chloride (500 ml) at 37aboutC.

Through certain time intervals samples were taken and using spectrophotometry (482 nm) were analyzed for the presence and amount of dye (E110), allocated from the kernel.

Obtained were the following:

Time, min Percentage allocation

180 0

190 0 200 0 210 0 220 0 230 0 240 0 310 5,06 330 59,76 360 102,93.

Test method of dissolution was also held in the same water (500 ml). The selection of the dye is registered via the half-time interval.

Evaluation of selection in vivo.

Evaluation of selection in vivo was performed using gamma iintegrate according to example 1.

Tablets were introduced seven zdorove, min 1 300 2 299 3 376 4 331 5 393 6 315 7 314 Average 332,6

Standard

the average error of 14.1

For each volunteer the place of discharge of the proximal colon.

Evaluation of selection in vivo was carried out also with the introduction of the same tablets six different healthy volunteers after a hearty meal.

The following results were obtained:

Volunteer Destruction

tablets, min 1 287 2 417 3 304 4 380 5 304 6 379 the Average value 345,2

Average

standard

error 21,8

The data obtained show that there is good correlation between secretion in vivo and in vitro and in terms of average values, the amount of food has no significant effect on time allocation.

The average standard errors shows that the delay interval of selection has minimum variance among different individuals.

Data selection in vivo additionally confirm in vitro data regarding the independence of the length of the delay interval selection the pH of the gastrointestinal tract.

P R I m e R 3. Preparation of labeled tablets according to the method similar to that described in example 2.

On the received image 0,57 RE 6000 0,06.

Then on the core with a protective coating caused hydrophobic layer (the receipt and application described in example 1) of the following composition, mg: Carnauba wax 24,6 beeswax 10,6 Surface-active additive 3,5

Hydroxypropylmethyl - cellulose 7,1

Evaluation of in vitro selection.

Evaluation of in vitro selection was performed according to the method of dissolution according to example 1.

The tests were carried out using 3,3% -aqueous solution of sodium chloride in water (500 ml) at 37aboutC.

Through certain time intervals samples were taken and examined using spectrophotometry (482 nm):

Time, min Percentage allocation 90 0 105 0 120 0 153 0 150 0 165 0 180 13,87 195 59,6 210 99,2.

The dissolution tests were also carried out in water without sodium chloride (500 ml). The selection of the dye was recorded after half-time.

Evaluation of selection in vivo

Evaluation of selection in vivo was performed using gamma scintigraphy according to example 1.

Tablets were administered to six healthy volunteers after a light meal.

Got the following results:

Volunteer Destruction

tablets, min 1 206 2 189 3 188 4 189 5 225 6 225 the Average value 203,7

Average

the standard deviation of 7.3.

P R I m e R 4. Preparation of labeled tablets with interoperation to assess in vivo location of the selection.

Prepared cores according to the method similar to that described in example 2.

On the resulting kernel has caused water-soluble protective film of the following composition, mg: Hydroxypropylmethyl cellulose 0,75 PEG 6000 0,08.

Then on the core with a protective coating caused hydrophobic layer (the receipt and application described in example 1) of the following composition, mg: Carnauba wax 30,0 beeswax 13,0 Surface-active additive 4.3 Hydroxypropylmethyl cellulose 8,6.

It was further deposited putting a coating of the following composition, mg: Interpolymer 8,8 Triacetin 0,8.

Evaluation of in vivo places of selection:

Evaluation in vivo of the space allocation of the active ingredient was performed using gamma scintigraphy according to example 1.

Tablets were administered to six healthy volunteers after a light meal.

Every volunteer selection occurred in the colon.

P R I m e R 5. Production of tablets containing as active ingredient abovementioned.

Manufactured kernel, using traditional methods of pressing, and each core was characterized silicon 0,42 Stearic acid 0,42.

The obtained kernel then struck a water-soluble protective film of the following composition, mg: Hydroxypropylmethyl - cellulose 0,20 PEG 6000 0,02.

Then the kernel with a protective layer were coated with a hydrophobic layer (the receipt and application described in example 1) of the following composition, mg: Carnauba wax 56,29 mg of the Surface-active additive 5,63 mg Hydroxypropylmethyl - cellulose of 11.26 mg

Evaluation of in vitro selection.

Evaluation of in vitro selection was performed using tests for dissolution according to example 1.

For tests used water (900 ml) at 37aboutC.

After a certain period of time, a sample was taken (10 ml) and analyzed using spectrophotometry (220 nm).

Obtained the following data: Time, min Percentage allocation 0 0 30 0 60 0 90 0 120 0 150 8,92 180 88,30 210 97,13.

P R I m e R 6. Manufacturing of tablets, comprising as an active ingredient is ibopamine hydrochloride.

Manufactured cores traditional methods of pressing, and each core had the following composition, mg: Ibopamine hydrochloride 42,00 Polyvinylpyrrolidone 1,65 Microcrystalline cellulose 6,55 Colloidal silica 0,40 Stearic acid 1,80 Lactose 33,70

On the floor of the pulp to 2.67 PEG 6000 0,30

Then on the core with a protective coating was deposited hydrophobic layer (its preparation and coating described in example 1) of the following composition, mg: Carnauba wax 29,33

Surface-active additive 2,93

Hydroxypropylmethyl cellulose by 5.87

Evaluation of in vitro selection.

Evaluation of in vitro selection was performed according to the method of dissolution as described in example 1 method.

In the tests used water (900 ml) at 37aboutC.

Through certain time intervals samples were taken (10 ml), which was analyzed using spectrophotometry (220 nm).

Obtained the following data:

Time, min Percentage allocation 0 0 30 0 60 0 90 35,11 120 101,43.

P R I m e R 7. Production of tablets containing as an active ingredient broxaterol hydrochloride.

Using traditional methods of compaction produced cores, each of which was of the following composition, mg: Broxaterol hydrochloride 0,569 Polyvinylpyrrolidone 3,00 Lactose 39,531 Starch 56,000 magnesium Stearate 1,000

Thus obtained core coated water-soluble protective film of the following composition, mg: Hydroxypropylmethyl - cellulose 0,90 PEG 6000 0,10.

Then on cores with a protective film Nana,24 beeswax 6,53 Surface-active additive 2,18 Hydroxypropylmethyl cellulose 4,35.

Evaluation of in vitro selection.

Evaluation of in vitro selection was performed according to the method of dissolution as described in example 1 method.

In the tests used water (500 ml) at 37aboutC.

Through certain time intervals samples were taken, which were analyzed using liquid chromatography high fracture with reversed phase (column: equivalent to 8 theoretical plates. 7 mm; eluent: phosphate buffer (acetonitrile; UV detector at 216 nm).

The following results are obtained:

Time (minutes ) Percentage allocation 0 0 30 0 60 0 90 0 120 60 150 98

P R I m e R 8. Manufacturing of tablets in which the active ingredient is broxaterol hydrochloride.

Using traditional methods of compaction produced cores, and the composition of each core conform to the following, mg: Broxaterol hydrochloride 0,569 Polyvinylpyrrolidone 3,000 Microcrystalline cellulose 95,531 magnesium Stearate 1,000.

Thus obtained core coated water-soluble protective film of the following composition, mg: Hydroxypropylmethyl cellulose 0,49 PEG 6000 0,06.

Then the kernel is covered with a protective film, struck a hydrophobic layer (its preparation and Nan is additive 2,70 Hydroxypropylmethyl cellulose 5,42.

Evaluation of in vitro selection.

Selection in vitro was assessed by the results of the dissolution tests carried out as described in example 1 method.

For tests used water (500 ml) at 37aboutC.

Through certain time intervals samples were taken, which were analyzed with pomomusings with reversed phase (column, equivalent to 8 theoretical plates, 7 m; eluent: phosphate buffer (acetonitrile; UV detector at 216 nm).

We obtained the following results:

Time, min Percentage allocation 0 0 30 0 60 0 90 0 120 47,3 150 77 180 100.

P R I m e R 9. Manufacturing of tablets, comprising as an active ingredient included broxaterol hydrochloride.

Core manufactured by the method similar to that described in example 1.

The obtained core coated water-soluble protective film of the following composition, mg: Hydroxypropylmethyl - cellulose 0,90 PEG 6000 0,10.

Then on the secure kernel struck a hydrophobic layer (the receipt and application described in example 1) of the following composition, mg: Carnauba wax 38,47 beeswax 16,47 Surface-active additive 5,47 Hydroxypropylmethyl - cellulose 10,98.

Evaluation of in vitro selection.

Selection in vitr"ptx2">

For tests used water (560 ml) at 37aboutC.

Through certain time intervals samples were taken, which were analyzed using GWHR with reversed phase (column, equivalent to 8 TT, 7 m; eluent; phosphate buffer/ acetonitrile; UV detector at 216 nm).

Got the following results:

Time, min Percentage allocation 0 0 30 0 60 0 90 0 120 0 150 0 180 0 210 0 240 0 270 33 300 67 330 102.

P R I m e R 10. Production of tablets containing as an active ingredient broxaterol hydrochloride.

Using traditional methods of compaction produced cores, and the composition of each core conform to the following, mg: Broxaterol hydrochloride 0,569 Polyvinylpyrrolidone 3,000 Lactose 77,431 Starch 18,000 magnesium Stearate 1.

The obtained kernel protective coating of water-soluble film of the following composition, mg: Hydroxypropylmethyl - cellulose 7,41 PEG 6000 0,82.

Then on the secure kernel struck a hydrophobic layer (the receipt and application of which is described in example 1) of the following composition, mg: Carnauba wax 22,16 beeswax 9,50 Surface-active additive 3,17 Hydroxypropylmethyl cellulose 6,33.

Evaluation of in vitro selection.

Selection in vitro was assessed by resull water (500 ml) at 37aboutC.

Through certain time intervals samples were taken, which were analyzed using GWHR with reversed phase (column equivalent TT, 7 m; eluent, phosphate buffer/ acetonitrile; UV detector at 216 nm).

The following results are obtained:

Time, min Percentage allocation 0 0 30 0 60 0 90 0 120 70 150 102.

P R I m e R 11. Manufacturing of tablets in which the active ingredient is broxaterol hydrochloride.

Prepared cores manner similar to that described in example 1.

The obtained core was covered with a hydrophobic layer (preparation and application as described in example 1) of the following composition, mg: Carnauba wax 18,96 beeswax 8,13 Surface-active additive 2,71 Hydroxypropylmethyl cellulose 5,42

Evaluation of in vitro selection:

Selection in vitro was assessed by the results of tests for dissolution as described in example 1 method.

For tests used water (500 ml) at 37aboutC.

Through certain time intervals samples were taken and analyzed them using GHUR with reversed phase (column 8 TT; 7 m; eluent: phosphate buffer/ acetonitrile; UV detector at 216 nm).

Obtained the following data:
< is as the active ingredient of diclofenac sodium salt (Diclofenac).

Manufactured using traditional methods of pressing, cores, each of which consisted of the following components, mg, Diclofenac sodium salt 50,0 Microcrystalline cellulose Polyvinylpyrrolidone 10.0 3.0 Lactose 25,0 Corn starch 74,5 magnesium Stearate and 1.5 Colloidal silicon dioxide 6,0 Karboksimetilirovaniya starch 20,0.

The obtained core coated water-soluble protective film consisting of the following components, mg: Hydroxypropylmethyl - cellulose 3,6 PEG 6000 0,4.

Then on cores with a protective film struck a hydrophobic layer (the receipt and application described in example 1) of the following composition, mg: Carnauba wax 62,0 beeswax 26,5 Surface-active additive 8,8 Hydroxypropylmethyl - cellulose 17,7

Evaluation of in vitro selection.

Selection in vitro was evaluated using tests for dissolution as described in example 1.

For tests used water (600 ml) at 37aboutC.

Through certain time intervals samples were taken, which were subjected to spectrophotometric analysis (276 nm).

We obtained the following data: Time, min Percentage allocation 270 0 300 12 330 87,5 360 99,2.

P R I m e p 13. Manufacturing of tablets: as activetab pressing, each of which consisted of the following components, mg: Naproxen 250 Polyvinylpyrrolidone 15 cornstarch 44 Stearate 5.

On the resulting kernel has caused water-soluble protective film of the following composition, mg: Hydroxypropylmethyl - cellulose 6,0 PEG 6000 0,7.

Then the kernel coated with a protective film coated hydrophobic layer (preparation and application as described in example 1) of the following composition, mg: Carnauba wax 104,8 beeswax 44,8 Surface-active additive 14,9 Hydroxypropylcellulose 29,9.

Evaluation of in vitro selection.

Selection in vitro was evaluated using tests for dissolution as described in example 1 method.

For tests used phosphate buffer (900 ml) at a temperature of 37aboutC.

Through certain time intervals samples were taken, which were subjected to spectrophotometric analysis (330 nm).

Received showed the following results:

Time, min Percentage allocation 360 0 390 16,9 420 73,7 450 104,3.

P R I m e R 14. Production of tablets containing as an active ingredient albuterol sulfate (Albuterol).

Manufactured kernel using traditional methods of extrusion, the composition Kai starch 16,1 magnesium Stearate and 1.0.

Thus obtained core was covered with a hydrophobic layer (receiving and manufacturing described in example 1) of the following composition, mg: Carnauba wax 32,3 beeswax 13,8 Surface-active additive 4.6 Hydroxypropylmethyl - cellulose 9,2.

Evaluation of in vitro selection.

Selection in vitro was evaluated according to the test results of dissolution as described in example 1 method.

The tests were performed in water (500 ml) at 37aboutC.

Through certain time intervals samples were taken, which were analyzed using GHUR with reversed phase (column 8 TT, 7 m; eluent: phosphate buffer/ acetonitrile; UV detector at 276 nm).

The following results are obtained:

Time, min Percentage allocation 180 0 190 18,6 200 50,8 210 71,4 220 92 230 101,2.

P R I m e R 15. Production of tablets containing as active ingredient Triazolam.

Using traditional methods of compaction produced cores, each of which contained the following components, mg Triazolam 0,125 Lactose 72,000 Microcrystalline cellulose 18,000 Colloidal silicon dioxide 0,300 Dioctylsulfosuccinate sodium 0,850 sodium Benzoate 0,150 Corn starch 4,750 magnesium Stearate 1,000.

On the received tacosa 0,90 PEG 6000 0,09

Then covered with a protective film cores caused hydrophobic layer (production and application described in example 1) of the following composition, mg: Carnauba wax 25,0 beeswax 10,7 Surface-active additive 3.6 Hydroxypropylmethyl cellulose 7,2.

Evaluation of in vitro selection.

Selection in vitro was evaluated by the method of dissolution as described in example 1 method.

The tests were carried out in water (500 ml) at 37aboutC.

Through certain time intervals samples were taken, analyzed using GHUR with reversed-phase column with 8 TT, 7 m; eluent water/ acetonitrile; UV detector at 222 nm).

The following data were obtained:

Time, min Percentage allocation 90 0 105 0 120 52,8 135 98,7 150 99,8.

P R I m e R 16. Manufacturing of tablets with controlled core allocation, in which the active ingredient contained mesalamine (Mesalamine).

Using traditional methods of compaction produced cores, each of which contained the following components, mg Mesalamine 300,0 Ethylcellulose 76,4 Crosspovidone 18,3 magnesium Stearate 6.2 Talc 10,4.

Thus obtained core coated water-soluble protective film of the following composition, mg: Hydroxypropylmethyl Yesenia and obtaining described in example 1) of the following composition, mg: Carnauba wax 140 beeswax 60 Surface-active additive 20 Hydroxypropylmethyl cellulose 40.

Next struck intestinale floor, consisting of the following components, mg: Interpolymer 47,0 Triacetin 1,3.

P R I m e R 17. Manufacturing of tablets with controlled core allocation, in which the active ingredient is tiotropia bromide (Cimetropium).

Using traditional methods of compaction produced cores, each of which contained the following components, mg: Tiotropia bromide 50 Lactose 125 Starch 73 Stearate 2.

On the thus obtained core caused water-soluble protective film of the following composition, mg: Hydroxypropylmethyl - cellulose 1,20 PEG 6000 0,12.

Then secure kernel coated hydrophobic layer (the receipt and application described in example 1) of the following composition, mg: Carnauba wax 67,0 beeswax 29,0 Surface-active additive 9.6 Hydroxypropylmethyl cellulose 19,0.

Next struck soluble in the intestine, the coating of the following composition, mg: Interpolymer 17,0 Triacetin 0,5.

P R I m e R 18. Manufacture of soft gelatin capsules to assess exposure in vitro.

Each capsule soderzhaniya hot coating in the fluidized bed at a temperature below the 50aboutWith the use of aqueous dispersions of the following mixture, mg: beeswax 23,37 Cetostearyl alcohol 5,85 Surface-active additive 2,93 Hydroxypropylmethyl cellulose 5,85.

Evaluation of in vitro selection.

Selection in vitro was assessed by the results of the test for dissolution as described in example 1 method.

The tests were carried out in water (500 mg) at 37aboutC.

Through certain time intervals samples were taken, which were subjected to spectrophotometric analysis (482 nm).

Obtained the following data:

Time, min Percentage allocation 0 0 30 0 60 0 90 0 120 0 150 78 180 102

P R I m e R 19. Assessment of the correlation between the thickness of the hydrophobic layer and the duration of the delay interval of the selection.

The results of the dissolution tests according to the description of example 1 was evaluated in vitro selection of active ingredient of the cores with a protective coating, i.e., deprived of a hydrophobic layer, obtained as described in example 2, and the hydrophobic layer are gradually increasing thickness obtained and applied in accordance with the description of example 1.

The hydrophobic layer consisted of a mixture of Carnauba wax, beeswax, surface-active is liczenie the thickness of the hydrophobic layer was expressed in the form of increased diameter tablets and a corresponding increase in her weight.

The dissolution was carried out in water (500 ml) at 37aboutC.

The beginning of the selection was detected by spectrophotometry (482 nm).

We obtained the following results:

Diameter, nm Increase Spacing

mass % delay

selection,

min 5,50 0 0 6,10 28 75 6,50 48 135 6,75 60 155 7,00 73 180

A similar test on the dissolution of the exposed core with a protective film, i.e., without the hydrophobic layer produced as described in example 5, and also covered with a hydrophobic layer of different increasing thickness, the receipt and application of which is described in example 1.

The hydrophobic layer consisted of a mixture of Carnauba wax, surfactant and hydroxypropylmethylcellulose taken in the weight ratios shown in example 5.

The beginning of the selection was detected by spectrophotometry (220 nm).

The following data were obtained:

Diameter, nm Increase Spacing

mass % delay

selection,

min 7,2 0 0 7,3 11 15 7,4 20 30 7,7 40 90 8,0 69 140

The data obtained show that there is a linear correlation between the increase in the thickness of the hydrophobic layer and the increase in the length of the delay interval selection and that this correlation does not depend on for oral administration, comprising a core and a shell, wherein the shell contains a hydrophobic material with a melting point of 50 - 90oWith surface-active substance with a pH value of 10 - 16 5 - 20 wt. percent of a hydrophobic material, if necessary, a water-soluble film-forming material in an amount of 5 to 30 wt. percent of a hydrophobic material.

2. Pharmaceutical form under item 1, characterized in that it contains a surfactant in an amount of 5 to 20 wt. % .

4. Pharmaceutical form under item 1, characterized in that it contains water-soluble film-forming material in a quantity of 1.5 to 20.0 wt. % .

5. Pharmaceutical form under item 1, wherein the hydrophobic material is a substance selected from the group of esters of higher fatty acids with higher alcohols, higher alcohols, higher fatty acids, esters of higher fatty acids with polyethylene glycol, or a mixture thereof.

6. Pharmaceutical form under item 1, wherein the hydrophobic material is a substance selected from the group of: Carnauba wax, beeswax, cetyl alcohol, stearyl alcohol, paraffin wax, microcrystalline wax, wax oil MESI.

7. Pharmaceutical form under item 1, characterized in that the surfactant is a fat polyethoxyethanol fatty acids with sorbitane or ethoxylated fatty alcohol.

8. Pharmaceutical form under item 1, characterized in that it comprises an outer layer from dissolving in the intestines coverage.

9. Method of producing solid pharmaceutical forms a programmable selection for oral administration by applying a coating on the core, wherein the core is a tablet or capsule, on which is applied a dispersion containing a hydrophobic material, a surfactant and, if necessary, a water-soluble film-forming material.

10. The method according to p. 9, characterized in that the applied outer layer of enteric coating.

Priority points:

04.07.90 on PP. 1,3-10.

12.12.90 on PP. 2 and 11.

 

Same patents:

The invention relates to medical equipment and can be used in health care to obtain aqueous extracts of medicinal plants, for example, infusions, decoctions and teas, Infundere device containing a reservoir with lid for filling sulcatas, the disk stops racks and perforated container formed by the surfaces of two hollow, coaxial, mutually inverted cylinders, and in the cavity of the smaller cylinder is the node transmitting motion made by ROMAGNOLO vertical, reciprocating movement, The technical result of the invention is to reduce the internal resistance of the extraction process due to changes in anatomical and morphological structure of raw materials by repeated mechanical deformation and, consequently, increase the degree of extraction of biologically active substances on 64-92% in relation to biologically active substances contained in the original dry raw materials

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a tablet decomposing rapidly in the buccal pocket and comprising a medicinal agent, excipient and saccharide with relatively lower melting point than that of a medicinal agent and excipient. Tablet is made by uniform mixing saccharide with low melting point with tablet mass to form bridge between particles of named medicinal agent and/or excipient through melting product followed by hardening mentioned saccharide with low melting point. Except for, invention relates to a method for making tablet decomposing rapidly in buccal pocket and comprising a medicinal agent, excipient and saccharide with relatively lower melting point than that of medicinal agent and excipient. Method involves: (a) the parent components of tablet comprising a medicinal agent, excipient and saccharide with relatively lower melting point that that of a medicinal agent and excipient are pressed under low pressure to provide the required tablet form; (b) pressed product obtained after stage (a) is heated to temperature when saccharide with low melting point is melted; (c) melted product obtained after stage (b) is cooled to temperature when melted saccharide with low melting point is hardened. Invention represents a tablet decomposing rapidly in buccal pocket and having the tablet strength providing its using in tablet-making machines for dosed formulations and giving the possibility for making tablet using common tablet-making machines, and to a method for making tablets. Except for, invention represents a tablet decomposing rapidly in buccal pocket being this table as compared with common tablets has enhanced tablet strength and improved frangibility without prolonged decomposing time in buccal pocket, and a method for tablet making.

EFFECT: improved making method.

63 cl, 4 tbl, 1 dwg, 21 ex

FIELD: pharmaceutical industry branch.

SUBSTANCE: installation includes housing jointly secured to telescopic struts. Inside housing driven latticed drum with pouring-over helix is mounted in hollow perforated shaft. Drive unit of drum is provided with unit for regulating rotation frequency. Installation is communicated with compressed air source and aspiration system. In order to set operation mode, inclination angle of drum axis is regulated due to changing height of struts and desired revolution number of drum is set.

EFFECT: enlarged functional possibilities of installation due to controlling its operation mode.

4 cl, 2 dwg

FIELD: medicine; medical engineering.

SUBSTANCE: method involves supplying target materials and core materials, carrying out target materials ablation with washed-out particle materials being produced and coating core materials with the washed-out particle materials. The method is applied under pressure of approximately equal to 10 torr or higher. Coating of thickness from one to several nm is applied at atmospheric pressure with pseudo-fluidized particle substance state, achieved by means of pneumatic pseudo-fluidization, being used.

EFFECT: improved pharmacokinetic drug properties.

22 cl, 22 dwg

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with pharmaceutical composition of bactericidal action. The composition suggested contains ciprofloxacin in the form of hydrochloride monohydrate, maltodextrin as a binding substance, sodium carboxymethyl starch as a disintegrating agent, silica gel, a lubricant at quantities mentioned in its formula. Ciprofloxacin tablets should be obtained due to pressing technique by applying the stage of moisture granulation. If necessary, the surface of tablets should be covered with a hydroxypropylmethylcellulose-based water-soluble membrane. Simultaneous application of maltodextrin as a binding substance and sodium carboxymethyl starch as a disintegrating agent enables to obtain ciprofloxacin-containing tablets of sufficient strength and quick release of active ingredient.

EFFECT: higher efficiency of application.

6 cl, 6 ex, 9 tbl

FIELD: medicinal industry.

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EFFECT: higher efficiency of manufacturing.

2 cl, 4 ex, 3 tbl

FIELD: pharmaceutics.

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EFFECT: higher efficiency of manufacturing.

1 cl, 3 ex, 1 tbl

FIELD: heat-exchanging equipment used in medicine, in particular, in blood transfusion stations.

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4 cl, 1 dwg

FIELD: medicine, pharmacy, pharmaceutical industry.

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EFFECT: improved and valuable properties of composition, improved method for preparing formulation.

3 cl, 5 ex

FIELD: medicine, pharmacy.

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EFFECT: improved and valuable pharmaceutical properties of compositions.

15 cl, 2 ex

FIELD: medicine, pharmacy.

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EFFECT: improved and valuable properties of formulation.

3 cl, 1 tbl, 1 ex

FIELD: medicine; medical engineering.

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EFFECT: improved pharmacokinetic drug properties.

22 cl, 22 dwg

FIELD: pharmaceutical agents.

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3 cl, 5 ex, 15 tbl

FIELD: medicine.

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EFFECT: provision of active substance release in desirable places of digestive tract.

28 cl, 7 dwg, 9 ex

FIELD: medicine.

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EFFECT: preparation of the stabilised antidementia drug.

20 cl, 11 tbl, 1 dwg, 7 ex

FIELD: medicine, pharmaceutics.

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3 cl, 1 ex

FIELD: medicine, pharmaceutics.

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4 cl, 5 ex

FIELD: medicine, pharmaceutics.

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EFFECT: capsule is stable at variable temperature and relative humidity, as well as resistant to decomposition of the active ingredients under exposure to light.

8 cl, 29 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: group of inventions concerns methods of reducing duration or severity of the inflammatory immune response in an individual, as well as a pharmaceutical composition containing carboxylated particles. Whereupon attached biologically active substances or attached antigenic molecules in the above particles are absent. Particles are particles of polylactic-co-glycolic acid (PLGA), polystyrene particles or diamond particles. Diameter of said particles is between approximately 0.1 mcm to approximately 10 mcm. Individual can have an autoimmune disorder, such as multiple sclerosis, scleroderma, type I diabetes, rheumatoid arthritis, thyroiditis, systemic lupus erythematosus, Reynaud syndrome, Sjogren's syndrome, autoimmune uveitis, autoimmune myocarditis or Crohn's disease, has ischemic reperfusion injury, atherosclerosis, suffered from myocardial infarction, is recipient of transplant, has psoriasis or dermatitis, or suffers from allergic disorders, such as eczema, asthma, allergic rhinitis or skin hypersensitivity. Individual can have a viral or bacterial infection, which can induce development of encephalitis or meningitis.

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12 cl, 13 dwg, 7 ex

FIELD: pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a method of producing a microencapsulated form of therapeutic peptide for oral application. Method involves administering undecapeptide U2 into lycopodium spores shells (LS) and further formation of alginate microcapsules (AMC) containing the said shell with peptide U2, for suppressing peptidase activity in the intestinal medium the system includes peptidases inhibitor - ovomucoid (OM), which is added to the alginate solution before the stage of forming AMC by ionotropic cross-linking, dispersion of LS with peptide U2 in water solution of sodium alginate and OM was injected in droplets into a settling bath containing an aqueous solution of CaCl2, then filtered, washed with water and dried under certain conditions, dimensions of the AMC make 800-900 mcm, inclusions of U2 and OM therein make 20-30 mcg/ml and 10-20 mcg/mg, respectively.

EFFECT: described method enables to obtain microencapsulated forms of therapeutic peptide for oral application in the form of two-level microcapsules having resistance to gastric acid medium and with prolonged release into the alkaline medium of the intestine.

1 cl, 1 dwg, 1 ex

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