Tf3 15 ff-oral-capsulas

Cápsulas / CapsulesJuan M. Irache

Farmacia y Tecnología FarmacéuticaUniversidad de Navarra

I. Formas Destinadas a la Vía Oral Cápsulas / Capsules

1. Cápsulas: IntroducciónPreparaciones sólidas, con una cubierta que puede ser dura o blanda y tenerforma y capacidad variables, y que generalmente contienen una única dosis de unp.a. Las cubiertas de las cápsulas son de gelatina u otras sustancias, cuyaconsistencia puede adaptarse por adición de sustancias como glicerol o sorbitol.También pueden añadirse otros como tensioactivos, opacificantes, conservantes,edulcorantes, colorantes y aromatizantes. Las cápsulas pueden llevar inscripcionesen su superficie. El contenido puede ser de consistencia sólida, líquida opastosa. Está constituido por uno o más p.a.(s), con o sin excipientes tales comodisolventes, diluyentes, lubricantes y disgregantes. El contenido no causa deteriorode la cubierta. Ésta, sin embargo, es atacada por los jugos digestivos, liberando elcontenido. Se pueden distinguir varios tipos:

- cápsulas duras- cápsulas blandas- cápsulas gastrorresistentes- cápsulas de liberación modificada

ENSAYOSUniformidad de contenido: Salvo indicación contraria o excepción justificada yautorizada, las cápsulas cuyo contenido de p.a. sea menor que 2 mg o menor que el2% de la masa total satisfacen el ensayo B de uniformidad de contenido parapreparaciones en dosis unitarias.Uniformidad de masaDisolución: Si se prescribe un ensayo de disolución, puede no ser necesarioensayo de disgregación.



Cápsulas duras: cubiertas formadas por dos partes cilíndricas prefabricadas, en las cuales uno de los extremos es redondeado y está cerrado y el otro está abierto. El principio o pa(s), generalmente en forma sólida (en polvo o granulados) se introducen en una de las partes de la cubierta, que se cierra por deslizamiento sobre ella de la otra parte. La seguridad del cierre puede reforzarse por medios adecuados.

Cápsulas blandas: cubiertas más gruesas que las de cubierta dura. Las cubiertasconstan de una sola pieza y son de formas variadas. La fabricación de las cápsulas,el llenado y el cierre se realizan normalmente en una sola operación.

Cápsulas gastrorresistentes: Se preparan llenando las cápsulas congranulados o partículas que tengan una cubierta gastrorresistente o bienrecubriendo cápsulas duras o blandas con una cubierta gastrorresistente(cápsulas entéricas).

Cápsulas de liberación modificada: Las cápsulas de liberación modificadaincluyen cápsulas de liberación prolongada y cápsulas de liberación retardada.

Sellos: preparaciones sólidas que consisten en una cubierta dura que contiene unadosis única de uno o más principios activos. La cubierta del sello es de pan ácimogeneralmente de harina de arroz y consiste en 2 secciones cilíndricas planasprefabricadas. Antes de su administración, los sellos se sumergen en agua duranteunos cuantos segundos, se colocan en la lengua y se tragan con un sorbo de agua.



2. Capsules: generalitiesThe capsule can be viewed as a container dosage form...

- Odorless- Tasteless- Easily swallowed- Elegant

Gelatin capsules (hard or soft)

Some shell capsules are made from materials other than gelatin...- Starch hydrolysate: "Capill"- Hydroxypropyl methyl cellulose ("Vegicaps" and others)

Such alternatives to gelatin will be of interest to those who,for religious, cultural or other reasons wish to avoid capsulesmade from animal derived components



Hard Gelatin vs Soft Gelatin "Softgels" CapsulesCriterion

Soft gelatin Capsules

Hard Gelatin Capsules

Shell

Plasticized (glycerin, propylene glycol, sorbitol)

Not plasticized

Content

Usually liquids or suspensions (dry solids possible)

Usually dry solids (liquids/ semi-solid matrices possible)

Manufacture

Formed/filled in one operation

Shells made in one operation and filled in a separate

process Closure

Hermetically sealed

(inherent) Traditional friction-fit;

mechanical interlock, banding and liquid sealing possible

Sizes and Shapes

Many Limited

Formulation Technology

Liquids Solids

Fill Accuracy 1-3% 2-5% (with modern automatic machines)



3. Hard gelatin capsulesAdvantages of Hard Gelatin Capsules

Rapid drug release possibleFlexibility of formulation

- Easily compounded- No need to form a compact that must stand up to handling- Unique mixed fills possible- Role in drug development / Role in clinical tests

Sealed HGCs are good barriers to atmospheric oxygen.Disadvantages of Hard Gelatin Capsules

Very bulky materials are a problemFilling equipment slower than tabletingGenerally more costly than tablets, but judge on a case-by-case basisConcern over maintaining proper shell moisture content

- Shell should have moisture content of 13-15%If too dry – become brittle/easily fracturedIt to moist – become too soft and can get sticky

- Unprotected capsules are best stored at 45-65% RH- Caution using strongly hygroscopic drugs

Cross-linking can affect soft/hard gelatin capsules, gelatin coated tablets



3.1. Hard capsules: sizes and capacities

Size Volume (mL)

Capacity (mg)

000 1.37 1096 00 0.91 728 0 0.68 554 1 0.50 400 2 0.37 296 3 0.30 240 4 0.21 168 5 0.10 104

Capacity (mg) at packing density=0.8 g/mLSpecials “containers” 00el: 1.02 mL, 816 mg 0el: 0.78 mL, 624 mg



3.2. Composition of Hard Gelatin ShellsComposition hard capsulesa. Gelatin

Bone Gelatin (Type B, alcaline gelatin; pI: 4.7-5.1)Skin Gelatin (Type A, acidic gelatin; pI: 7-9)

Bloom strength (Poder gelificante): a measure of relevance to cohesive strength of gelatin filmThe weight in g required to depress a plunger 12.7 mm diameter 4 mm into a 6.67% gel held for 17 hours at 10 degrees (O.T. Bloom, 1925)

Typically for hard capsules: 200-260 "bloom-grams"Viscosity: single most important factor controlling shell thickness

Capillary viscometer; 6.67% soln.Typical range 25-45 millipoise.

b. Waterc. Dyes and other colorants: http://www.capsugel.com/amer/color/catalog.phpd. Opaquing agent (TiO2)e. Preservative:

no necessary if work under GMP conditionswater content of 13-16%: no possibility for microbial contamination



3.3. Hard capsules manufactureThe Dipping Process of Making Hard Gelatin Capsules: similar process to that patented in 1846

a. Metalic mouds are dipped in a warm gelatin bathb. A film of gelatin is formed around c. Dry process of gelatind. Extractione. Cutting at the desiring sizef. Sealing and positive closure

Tamper resistance/tamper evidencePrevents inadvertent separation on

handling/shippingMakes liquid/semi-solid filling of hard

gelatin capsules possibleSealed capsules are excellent barriers to O2

Qualicaps GroupCapsugel





Types of hard gelatin capsules: mechanically interlocking Caps and Bodies

Interlocking rings or bumps molded into the cap and body side-wallsPosilok (Shionogi): two-piece gelatin capsule with its mechanical lock made by indentations in the cap and body. The vented cap indentation allows air to escape when capsule is closed on high-speed filling machines. Snap-Fit and Coni-Snap® (Capsugel)Lox-it (Pharmaphil)

Traditional Prefit Locked





Pre-lockedposition

Sealedposition

Coni-Snap® (Capsugel)



Types of hard capsulesQuali-V® (HPMC) Shionogi Qualicaps / VCaps (HPMC; Capsugel): two-piece hard shell capsule derived from non-animal sources, which satisfy vegetarian and cultural needs. Additional benefits: chemical stability and low moisture content –making it an attractive alternative for hygroscopic formulations.Licaps® Capsules: gelatin capsules for containment of liquids and semi-solids.PCcaps™ Capsules: very small size gelatin capsules that are ideal for oral dosage to rodents in pre-clinical studies.Press-fit® Gelcaps: high-gloss gelatin coating that encases a caplet core. They combine the best qualities of a gelatin capsule with the density of a tablet. DBcaps® Capsules: two-piece gelatin capsules that are designed for double-blind clinical trials. The shorter length facilitates ease of swallowing.

DBcaps Licaps Press-fit



Types of hard capsulesDRcaps Gastro Resistant Capsules: HPMC capsules resistants to the acidic conditions of the stomach without the addition of any type of coatings.NPcaps Pullulan Capsules: from pullulan, a water-soluble polysaccharide. Capsules highly impermeable to oxygen transmission. OceanCaps Fish Gelatin Capsules: marine-based capsule.Pearlcaps Pearlescent Capsules: shiny, iridescent capsules. Differentiate your products, ideally suited for the cosmeceutical market. Available in gelatin and HPMC capsules.



Sealing and Welding MethodsBanding

Original banded hard gelatin capsule - Parke Davis' "Kapseal"Modern banding process - Shionogi's Qualiseal

Liquid sealingCapsugel's Licaps

Licaps



3.4. Formulation of hard capsulesActive IngredientHighly water soluble drugs exhibit few formulation problems in terms of drug release from either tablets or capsules.Micronization of poorly soluble drugs can improve dissolution from tablets and capsules.

Affect on flow and mixing– Adsorption to surfaces of filler particles (a form ordered mixing) may help

Effective surface area may be reduced by agglomeration of micronized particles– Addition of a wetting agents (surfactants) may help.

Filler (Diluent)Fillers include lactose, starch, dicalcium phosphate, Starch 1500

Forms modified for direct compression tableting are useful for flow/compactibility - especially important for plug forming machines.

Consideration the solubility of drug in selecting a filler.Water soluble fillers are preferred for poorly soluble drugs: In certain instances, a large percent of soluble filler in the formulation has slowed the dissolution of a soluble drug.

Possible incompatibilitiesClassic example: Tetracycline formulated with calcium phosphate.



3.4. Formulation of hard capsulesLubricantsGlidants (colloidal silicas such as Cab-O-Sil, Aerosil)

Optimum concentration generally <1%, typically 0.25-5.0%.True Lubricants and Antiadherents (e.g. Metallic stearates, stearic acid)

Best lubricants are hydrophobic– Increasing concentrations usually retard dissolution.– Blending time an issue with laminar lubricants.avoid overmixing

Effect is exacerebated at higher degrees of compaction.

Disintegrants (4-8%): sodium starch glycolate; croscarmellose sodiumSpeed up drug dissolution by... Promoting liquid penetration (wicking)

Promoting deaggregationEfficiency often improves with increased tamping force.

Crospovidone not as effective in capsules at equivalent concentrations

Surfactants: sodium docusate (0.1-0.5%); sodium lauryl sulfate (1-2%)Speed up dissolution by... Increasing wetting of powder mass (can overcome the waterproofing effect of hydrophobic lubricants)



3.5. Manufacturing steps



3.6. Capsule filling machines

Output Capacities of Some Capsule Filling MachinesSemi-automatic No. 8 Machine 120,000-140,000/ShiftFully Automatic Zanasi Z-5000/R3 150,000/h

MG2 G100 100,000/hBosch GKF 3000 180,000/hOsaka R-180 165,000/h

TODAY, HARD GELATIN CAPSULES ARE MOST OFTENFILLED BY AUTOMATIC MACHINES WHICH RESEMBLETABLET PRESSES TO THE EXTENT THAT -THEY FORM POWDER PLUGS BY COMPRESSION, AND EJECT THEM INTO EMPTY CAPSULE BODIES



Dosator Principle



Dosing Disc Principle



MG2 FuturaDosator Machine36,000 caps/h



Banding machine

Capsule-fillingmachine



Manual filling machine



https://www.youtube.com/watch?v=fF1bJ6jaZw8

Semi automatic filling machine



Manual filling machine

https://www.youtube.com/watch?v=26OIri_HEBohttps://www.youtube.com/watch?v=9rzoHH8nlvQ

Mini beads Granules LiquidsMini tabs Semi-solids Powders



3.7. Ensayos cápsulasDisgregación Cápsulas duras: Utilizar agua R. Si está justificado, puede emplearse ácido clorhídrico 0,1 M, o bien jugo gástrico artificial R. Hacer funcionar aparato durante 30 min y examinar el estado de las cápsulas. Las cápsulas satisfacen el ensayo si las 6 se disgregran.Cápsulas blandas: Utilizar agua R. Si está justificado, puede emplearse HCl 0,1 M, o bien jugo gástrico artificial R. Hacer funcionar el aparato durante 30 min y examinar el estado de las cápsulas. Las cápsulas satisfacen el ensayo si las 6 se disgregran.Cápsulas gastroresistentes: Utilizar HCl 0,1 M y hacer funcionar el aparato durante 2 h, o cualquier otro tiempo que se autorice. El tiempo que las cápsulas resisten el medio ácido varía entre 2-3 h. Nunca menor de 1 h. Ninguna cápsula muestra señales de disgregación o fisuras que permitan la salida de su contenido. Reemplazar el ácido por disolución tampón de fosfato a pH 6,8 R. Cuando se justifique, puede emplearse una disolución tampón a pH 6,8 con polvo de páncreas. Hacer funcionar el aparato durante 60 min y examinar el estado de las cápsulas. Las cápsulas satisfacen el ensayo si se disgregran las 6.

Disolución. Cápsulas gastroresistentes: Para cápsulas preparadas a partir de granulados o partículas con recubrimiento gastrorresistente, se efectúa ensayo adecuado que demuestre liberación del p.a(s).



4. Soft gelatin capsules (Softgels)

Similar to hard gelatin shell, except plasticizer is incorporated (sorbitol, propylene glycol, glycerin)

Usually filled with liquids or suspensions (dry solids are possible)

Advantages of Soft Gelatin CapsulesHigh Accuracy/precision possibleHermetically sealed (inherently)Possible bioavailability advantagesReduced dustiness; lack of compression stage in

manufacturePossible reduced gastric irritancy compared to

tablets and hard shell capsulesSpecial packages available



Disadvantages of Soft Gelatin Capsules

Generally, product is contracted out to a limited number of specialty houses,e.g. Scherer, Banner.

Generally more costly to produce than tablets or hard shell capsules

More intimate contact between the shell and contents than with dry-filled hard shell capsules - stability a concern.

Not adaptable to incorporation of more than one kind of fill into the same capsule (compare with hard shell capsules)



Softgel sizes and shapes



6.5.1. Formulation of soft capsules

Gelatin: Bloom strength 150 - 200 bloom gramsPure liquids, mixtures of miscible liquids, or solids dissoved or suspended in a liquid vehicle.VehiclesWater immiscible non-volatile liquids

vegetable oilsMineral oil not recommended for drug formulations.

Water-miscible, non-volatile liquidsLow molecular weight PEG'sNonionic surfactants such as polysorbate 80

Limitations of liquid contentsWater can not exceed 5% of contentspH must be between 2.5 and 7.5Low molecular weight water soluble and volatile compounds must be

excludedAldehydes, in general, must be excluded (Cause cross-linking)Contents must flow under gravity at < 35ºC



6.5.2. Soft capsules manufactureOriginal Rotary Die Process (R.P. Scherer: 1933); troquel rotatorio

Only for pumpable fillsAccogel Process (Stern Machine) - Lederle: 1948

A rotary die process for filling powders/granules into soft capsules

a. Blending powdered gelatin and other ingredients with warm water in a gelatin melting tank:

after hydration the powder becomes a thick “syrup” called a gelatin mass. the key to mixing gelatin is to heat, blend and deaerate quickly

b. Filtration and store in portable heated stainless steel tanks gelatin mass should be kept at 65º C

c. Spreader Boxes - The gelatin mass is applied to both sides of the machine simultaneously by a set of spreader boxes which regulates the gelatin thickness from 0.6 to 0.7 mm as it is spread on the cooling drum. The gelatin is cooled while the thin layer of gelatin rotates with the cooling drum. d. Lubrication System – Prior to encapsulation the ribbon must be coated with a thin layer of oil to prevent sticking during the filling and sealing process.

lubricants are: digestible mineral oil, fractionated coconut oil, Miglyol 812



http://www.kwangdah.com/kde-300.htm



Rotary Die process

6.5.2. Soft capsules manufacturee. Medicine Filling Pump: Before the capsule can be formed and sealed, it must be filled. The material to be filled flows by gravity and is injected between dies

Individual plungers pull a precise amount of material f. Capsule Forming & Filling – After the 2 halves of gelatin have been cooled and lubricated, they meet together at the forming and filling station. Dies that contain small pockets in the shape and size of the capsule to be made help form and seal. While the capsule is being filled, it is also simultaneously being sealed and cut from the ribbon.g. Drying: capsules are very soft due to the high moisture content. Reduce to 6-10% h. Polishing (for printing) i. Packaging: bulk containers, bottles or blister packaging



1. Gelatin ribbon2. Rotary die3. Filling Wedge4. Filled capsule5. Webbing6. Pumping mechanism

Bibliografía complementaria• Cápsulas

– Qualicaps: http://www.qualicaps.com/about/default.aspx– Capsugel: http://www.capsugel.com/– Laboratorios Juste: http://www.juste.es/– Banner: http://banpharm.com/

• Excipientes – Basf Pharma: http://www.basf-pharma.com/ – Beghin-Say: http://www.beghin-say.fr/pharmafr/– Borculo Domo Ingredients: http://www.borculodomo.com/milk/lactosaesp/– Brenntag NV: http://www.brenntag.be/– Colorcon: http://www.colorcon.com/– Degussa Pharma: http://www.degussa4pharma.com/

http://www.aerosil.com– DMV International: http://www.dmv-international.com/default.asp– FMC Biopolymer: http://www.fmcbiopolymer.com/– Friesland Foods Domo: http://www.domo.nl/– International Specialty Products (ISP): http://www.ispcorp.com/– JRS Pharma: http://www.jrspharma.com/– Merck Farma y Química, SA:

http://www.merck.de/servlet/PB/menu/1378040/index.html– Meggle Pharma: http://www.meggle-pharma.de/es/– PFormulate: http://www.pformulate.com/– Roquette Pharma: http://www.roquette-pharma.com/



• Máquinas para dosificación de cápsulas– Axus: http://www.axus.cc/– Bosch: http://www.boschpackaging.com/site/home/index.aspx– CapPlus Technologies: http://www.capplustech.com/ – Torpac: http://www.torpac.com/filling_machines.htm– Karisma Pharma Machines: http://www.karishmapharmamachines.com/– Health Star:

http://images.google.com/imgres?imgurl=http://www.healthstar.net/images/UsedMachines/Large/28352-289-01.jpg

– Zhejiang Fuchang Machinery: http://www.chinafuchang.com– Maneklal: http://www.maneklalexports.com/English/PharmaMc.htm

• Aparatos para ensayos :– Electrolab: http://www.scientificdealers.com/electrolab/ – Erweka: http://www.erweka.com/EN/index.php– PharmaAlliance: http://www.pharma-alliance.net/index.php– Quantachrome Instruments: http://www.quantachrome.com/index.htm– Sotax: http://www.sotax.com/index3.html

Bibliografía complementaria



Health & Medicine

Tf3 15 ff-oral-capsulas