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"KNOW-HOW" OF GELATINOUS CAPSULES
Theoretical clause about manufacture of gelatinous capsules.
Some features of technology of reception of capsules, selection
Compositions of gelatinous weights and napolnitels.
The big variety of preparations in the form of capsules, distinction
Physical and chemical characteristics inkapsuliruemyh substances demands
Enough a wide variety in approaches to creation of preparations in
To this medicinal form.
To reception of shells of capsules apply film-forming
The high-molecular substances, capable to give elastic a film,
Described by the certain mechanical durability. Such
Materials simple and complex ethers can be casein, zein,
Cellulose and some synthetic polymers (for example, a copolymer metakrilamida and metakrilovoj acids, etc.)
[1]. However wide practical
Applications for pharmaceutical capsules have not found these substances, and
Therefore till now a farmaceutical industry
Uses mainly gelatinous capsules.
Gelatin represents a product of partial hydrolysis of collagen-
The substance of the albuminous nature forming distributed in the nature
The main component of a connecting fabric pozvonochnyh (before
In total in a leather, bones, sinews, horns, hoofs). In his basis
Molecules the circuit formed by 19 amino acids lays polipeptidnaja,
Basic of which are glitsin (up to 30 %), and also alanin,
prolin, gidroksiprolin, glutamin
[2]. Collagen of bones and skins subject
matseratsii and clearing by acids or alkalis which split it gidroliticheski on practically not ramified aminokislotnye chains
Various length, that is gelatin. Depending on length of a circuit
Gelatin has molecular weight from 40000 up to 100000. Used
The way of decomposition defines the nature of an end-product,
Designated as gelatin And (acid) or gelatin In (alkaline).
These types differ among themselves on some physical and chemical
To parameters and abroad, as against the former USSR, in manufacture
Pharmaceutical capsules use mixes of gelatin And and V.Smes
Allows to receive weights for manufacturing shells of capsules with most
Optimum reologicheskimi characteristics (in particular on
To parameters of durability, viscosity, rN, to the maintenance of iron, etc.).
Except for gelatin, in structure
Shells there is a lot of auxiliary components:
Softeners - the substances giving necessary elasticity
To shells of capsules. 1999-2011ost widely for these purposes it is used
Glycerin, can be applied also sorbite, polietilenglikoli, a number
Other substances or their compositions. The quantity of softeners can
To reach 50 % from a lump of capsules; preservatives - substances,
Preventing an opportunity of microbic impurity gelatinous
Capsules. 1999-2011ost rationally for these purposes to use a mix methyl
And etilparabena (nipagin and nipazol), application is possible also
Salicylic and sorbinovoj acids, their some derivatives;
Other additives - substances, which introduction in structure gelatinous
Weights for reception of shells of capsules in some cases is
Necessary.
Among them it is necessary to note the following:
Dyes - now all capsules, with rare exception,
Are painted for giving of more aesthetic kind by him. Different
Colourings are convenient and at release of various names of preparations in
To the form of capsules as allow to distinguish production on color. In
Quality of dyes substances natural can be used
Origins (karminovaja an acid, a chlorophyll, b-carotin, etc.),
Inorganic pigments (yellow, red and black okis iron,
Dioxide of the titan), and also the organic dyes resolved to
To medical application (thus their quantity in one capsule not
Exceeds, as a rule, 50 mkg) [3];
zamutniteli - the substances, allowing to receive opaque capsules,
Due to ability to form in gelatinous weight steady
melkodispersnuju suspension. 1999-2011ore often for these purposes use
Dioxide of the titan, less often - gidroksid aluminium, a carbonate of calcium [3, 4];
Water-absorbing agents - the substances, allowing to prevent
An opportunity of procrastination of a moisture from the shell of a capsule gigroskopichnymi
Substances which can be used at filling capsules. For
This purpose is recommended to use polipeptidy, oligosaharidy,
Starch and his derivatives, some other substances [5, 6];
dezintegranty - the components promoting preservation of a parameter raspadaemosti of capsules at long storage (gelatin, being
A product of processing of collagen, possesses property of "ageing"), and
Also to achievement of fast liberation of contents from medicinal
Forms. In this quality amino acids, proteins can be used,
Casein, kroskarmelloza, twins, a hydrocarbonate of sodium [7, 8, 9, 10].
For achievement fast raspadaemosti shells of capsules can be
Also the technology dispergirovanija some gases is applied
(oxygen, nitrogen, okis carbon, argon and others) in gelatinous weight
(that, except for other, allows to save a material of the shell) [11,
12]. Deserves also attention offered by the Japanese scientists
An original way of processing of the gelatin amber anhydride
[13];
Sliding - the agents preventing possible slipanie of capsules
(it is actual first of all for the soft capsules sold in the countries with
A hot climate and at impossibility of observance of rules of storage of this
The medicinal form), - in particular D-mannit, D-sorbite, ksilit
[14, 15]. Can be entered and other additives.
During becoming kapsulnogo manufactures it was offered
Some ways of their reception, from which now in
The advanced kind three are used:
A method of immersing ("makanija") which essence consists in
Manufacturing shells of capsules by means of special "makalnyh" frames
With the pins, capsules displaying the form. Pins fall in rasplav
Gelatinous weight which stiffens on them the thin shell.
The shell remove, form (fix the form drying at certain
Modes) also fill napolnitelem, or at first fill, and then
Form - depending on a kind of received capsules: firm or
Soft. Thus, if for reception of soft capsules (with drop
zapajkoj) the method is low-productive, labour-consuming and is applied today
Only in laboratory conditions, for reception of firm capsules he
Has found wide application in the industry, being, as a matter of fact,
The only thing. Today in the world it is totaled over 400 automatic devices on
To reception of firm gelatinous capsules (are issued mainly
The American firms - "Elanco", "Parke-Davis", "Colton", Canadian
« Capsule Technology International », German « Hofliger und Karg »,
Some other)
[16]. Despite of a variety of firms, them
Automatic devices differ from each other insignificantly (quantity
Pins, the form of frames - holders, productivity, which
Changes from 36 up to 72 thousand capsules at one o'clock, etc.).
A method of punching, or modern updating: rotatsionno-matrix.
It is applied to manufacture of soft gelatinous capsules, being
The most rational for their reception in conditions industrial
Manufactures. The principle of a method consists in reception originally
A gelatinous tape (matrix), from which under presses or on valkah vyshtampovyvajut capsules at once after their filling and zapajki.
The automatic devices working on this method, carry out all operations with
High accuracy (yo 3 %) and the big productivity (from 3 up to 76
Thousand capsules at one o'clock), and also allow to receive capsules various
Forms, a wide range of capacity and with napolniteljami various
Consistences (mainly liquid and pastelike). In the present
Time in the world works about 400 automatic devices on manufacturing capsules
A rotatsionno-matrix method (are issued by Italian firm " Pharmagel ",
Canadian « Capsule Technology International », Korean « Lucky Gold
Star », etc.)
[17.] Drop - the youngest method,
For the first time appeared in 60th years (it is introduced into manufacture Dutch
Firm « Interfarm Biussum »). Allows to receive soft seamless
Gelatinous capsules of strictly spherical form. His principle
Consists in expression under pressure from concentric
A tubular atomizer simultaneously rasplava shells and liquid
napolnitelja which fills in a capsule as a result of biphase
A concentric stream; zapechatyvanie capsules occurs for the bill
A natural superficial tension of gelatin. The method is enough
High-efficiency (up to 60 thousand capsules at one o'clock) and exact
(deviations in a dosage napolnitelja does not exceed yo 3 %), however from it
The help it is possible inkapsulirovat only legkotekuchie liquid not water
napolniteli with rather small top limit of batching (up to 0,3
Ml) [17]. However last development spent Japanese and
The Israeli experts, have already allowed to receive capsules with
Considerably higher top limit of batching (up to 0,75 ml)
[18.]
As is known, napolnitel for capsules can have various
A consistence. Thus contents of soft capsules are legkotekuchim or pastelike - oils, oil or others not water
Solutions, suspensions, pasto-, maze-or geleobraznye napolniteli.
Some foreign firms and researchers spent jobs
On manufacturing the soft gelatinous capsules containing firm
napolnitel (powders or their mixes) [19], however practical
Distributions have not received these development, appearing
Irrational.
At the same time practical application is found with firm capsules,
Filled with liquid contents [20, 21] (it is fat-soluble more often
Vitamins). Thus for prevention of an opportunity vytekanija
napolnitelja make tight zapechatyvanie junctions
Cases and kryshechki, that can be achieved by various ways:
Mechanical thermal welding, imposing of a bandage slozhnokomponentnymi the solutions containing gelatin, ultrasonic
Welding, low-molecular thermal hermetic sealing, drawing
A film covering on a surface of a capsule [20, 22, 23].
If at reception soft
Gelatinous capsules their manufacturing and filling are made
Simultaneously, for firm gelatinous capsules these processes
Are carried out separately: at first the capsule turns out and formed, and
Then it is filled napolnitelem on the separate equipment (and, more often
Everything, on the other manufacture).
Devices on filling firm gelatinous capsules usually
Carry out the following operations:
Focused installation of empty capsules in jacks dozatorov
(kryshechkoj upwards);
Opening capsules (separation of the case and kryshechki);
Filling the case of capsules by contents;
Closing capsules (dense connection of the case and kryshechki);
Pushing out of the filled capsules in the receiver.
Besides on completely automatic devices it is made
Also otbrakovyvanie the unopened capsules, obespylivanie, removal at
The help special otsosov scattered napolnitelja, cleaning
Cartridges.
Devices on filling firm capsules can be:
Manual or semi-automatic which are intended
Mainly for needs of drugstores, laboratories or small
Manufactures (possible productivity - up to 6 thousand capsules in
Hour). Filling on them is carried out by a method nabivanija, thus
The weight for filling a capsule should be proportional to its volume;
Completely automatic - for industrial production; thus
The piston method of filling with use dozatorov is applied, and
Filling devices can be with periodic or continuous
Moving.
To filling capsules pelletami or microcapsules can be applied
The devices making filling by methods nabivanija, piece
Fillings, with use double zaslonki, with use
The piston, with use of dosing cylinders, and also with
Use of a dosing tube.
Filling capsules by tablets or drops (or their combinations)
It is carried out with use zaslonki.
In case it is necessary to fill in firm gelatinous capsules
By liquids or pastelike napolniteljami, are applied special
Pumps.
Except for farmakologicheski active substance in structure of weight for
Fillings capsules with the purpose of giving to her necessary technological
Characteristics, and also the task, if necessary,
Biopharmaceutical properties auxiliary components are entered,
Which should be biologically indifferent. 1999-2011ore often
Are applied:
napolniteli, or thinners - give to weight for filling capsules
Necessary optimum volume. For these purposes at manufacturing
Preparations in the form of firm capsules are applied sugar dairy,
Microcrystalline cellulose (MKTS), calcium phosphate dvuhosnovnyj and
Other substances which allow to adjust volumetric density and
To give napolnitelju necessary flowability, and MKTS, besides
Allows to slow down process vsasyvanija, that is important for prolongation of action of a preparation. For soft gelatinous capsules in
Quality indifferent napolnitelja can be used
Vegetable oils, mixes polietilenoksidov, much less often-
silikonovye oils and slozhnokomponentnye the structures including, except for
Above-stated, glycerin, propilenglikol, the twin - 80 and others [24];
Sliding - give napolnitelju for firm capsules necessary
Flowability. Are usually used calcium or magnesium stearat,
A stearin acid, talc. Their quantity, as a rule, makes
0,5-2,0 % [25];
dezintegranty - the substances promoting deagregatsii
inkapsulirovannoj powder weight. It is established, that stamped
Powders in capsules break up in 2 times longer, than freely
Filled, but the difference becomes insignificant at introduction dezintegrantov [7]. In this quality apply basically of aeroforces
(kolloidnaja dioxide of silicon), talc, a carbonate of calcium;
tiksotropy - substances which give necessary fluidity
napolniteljam: reduce viscosity of pastelike weights at allowable
Heating (in this quality it can be used, in particular,
etilovyj spirit) [26], or increase viscosity legkotekuchih weights
For filling capsules (it is important first of all for filling firm
Gelatinous capsules, in structure of weights for which filling can
To be entered with this purpose polietilenglikoli, voski, soya lecithin and
Other) [27, 28];
If necessary can be entered and other additives.
The increasing distribution to last years is found with capsules with
The set properties on liberation of working substance is
kishechnorastvorimye capsules (with liberation medicinal
Substances in intestines) and so-called capsules - retard (with
Prolonged). Creation kishechnorastvorimyh
Medicinal forms it is carried out with the purpose of prevention
Liberation of an active component in a stomach (for maintenance
Stability of medicinal substance, prevention of his decrease
Concentration under action of gastric juice, reduction possible
By-effects, prevention possible undesirable
Neutralizations of gastric juice, etc.).
Reception kishechnorastvorimyh capsules can
To be carried out in several ways:
Introduction of so-called hardeners in structure of weight for reception
Shells of capsules. In this quality the some people can be applied
Aldehydes, alginat sodium, other substances [29, 30]. A method not
Has received a wide circulation;
Processing shells of the ready and filled capsules certain
Substances for giving to her the greater hardness (for example
Formaldehyde) [31] with the purpose of prolongation of time raspadaemosti
Capsules that she has had time to get in thin intestines intact.
This method now also practically is not applied because of
The irrationality and nebezopasnosti for industrial
The personnel;
Drawing film coverings on the ready and filled capsule. For
Coverings of capsules use special structures, the basic
Which components are shellac, derivatives more often
Cellulose (for example simple or complex ethers), polimetakrilaty,
Copolymers (styrene and maleinovoj acids, vinilatsetata and kapron
Acids, etc.) natural voski, alginat sodium and others [22, 32,
33]; giving kishechnorastvorimyh properties itself napolnitelju-
kishechnorastvorimye film coverings are rendered directly on
Granules, pellety or microcapsules. Alongside with previous, this method
For today it is most used in manufacture
kishechnorastvorimyh preparations in the form of capsules.
For giving prolonged properties kapsulirovannym to preparations
Use technological receptions of introduction of special components
In structure napolnitelja for capsules. Usually apply combinations
The substances interfering fast liberation working
Components of the medicinal form among which are most used
Indifferent for an organism of the person akrilovye polymers (Eudragit
Several stamps), derivative cellulose (microcrystalline
Cellulose, oksipropilmetiltselljuloza, metiltselljuloza, etc.),
Some other substances [33, 34, 35].
All the above variety in approaches to creation of compositions
Gelatinous capsules and technology of their reception it is necessary to take into account
By development of medical products in the form of gelatinous capsules.
Each medicinal substance, possessing inherent only to her
Certain physical and chemical and required pharmacological and
farmakokineticheskimi properties, demands an individual approach at
Creation of the medicinal form. It also is considered by authors
By development kapsulirovannyh medical products.
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