Dosage form

Problem – want oral dosage form. – but has short half life (3-4hr) Solution – oral dosage form with extended release which releases drug slowly so that the plasma concentrations are maintained at a therapeutic level for a prolonged period of time (usually between 8 and 12 hours). Recent extended release formulations possible pH-sensitive multiparticulate drug delivery system – how it works: – a nano-suspension was made from with the drug, and then chitosan bead were made, which were degradable selectively in the colon Advantage – area specific absorption of drug.

And prevent drug form degradation, for non-soluble drugs Disadvantage – not for water soluble drugs (have to make suspension), not for sustained release, Modified Push-pull osmotic systems – – how it works – the system has two compartments, one is hydrogel, and the other is for non-watersoluble drugs with orifice, which diffuses out with the hydrogel absorbs water and pushes the drug out slowly Advantage – can use two drugs, one being water soluble can be incorporated into the expandable hydrogel. Sustained release.

Disadvantage – its better to use with two drugs, or no point of this, epensive, Controlled drug diffusion for oral extened release by using micelle-forming properties and counter –charge polymer. -how it works: – a highly water soluble drug was added to a gel forming polymer matrix but with a counter polymer which slows down drug diffusion out of the matrix Advantage – for water soluble drugs, sustained release, simple to make Disadvantage – not for all water soluble drugs, make sure that counter-charge polymer does not bind with too high affinity to the drug, and does not interact with the drug chemically. Our drug is not charged.

Aqueous-core microcapsules with a defined PLG shell. How it works: – encapsulate the drug in microcapsule or in microsphere can either produce a pulsatile release with a surface eroding polyanhydride shell, of a bulk-eroding polyester may provide sustained drug released through the matrix. Advantages – precision particles, sustained release, make different shell thickness to change release rates and times. Disadvantages – mainly for proteins, expensive, hard to scale up and guarantee size uniformity. Entrapment efficiency.

– * Hydrophilic Matrix Systems – or hydrogels How it works: -the hydrophilic colloid takes in water and swells to form a hydrated matrix layer – which controls the drug diffusion out of the matrix. Basically, drug is released in 2 ways, through the erosion of the gel matrix, and through diffusion out of the gel matrix.

Hydrogel Technology Hydrogels are hydrophilic macromolecular networks that, after swelling, maintain their shape due to permanent links. The very high water content and special surface properties of the swollen form give them the ability to simulate natural tissues.

Hydrogels are very versatile materials [1]. Much interest has been expressed in the application of hydrogels for controlled drug delivery, because they have been shown to be excellent carriers for the release of drugs and bioactive compounds. Particularly when used in a dehydrated state, they undergo glassy to rubbery transition. Drug delivery technologists usually tend to consider all hydrophilic delivery systems as hydrogels. In fact, the most widely used polymers for drug delivery control, particularly in oral applications, are swellable polymers.

These polymers allow the preparation of drug delivery systems that, after transition from the glassy to the rubbery state, differ from hydrogel in so far as they do not maintain a permanent shape. In any case, a common feature is the swelling of the polymer that often results from the glassy-rubbery transition of the dry form. This last property is used as a drug delivery control mechanism. Cellulose derivatives, for example, become classical polymers in pharmacy because of their swelling capacity, low toxicity, acceptable cost and wide availability.

Numerous hydrophilic drug delivery products have been formulated, mainly as matrices, using cellulosic polymers, and they are called “swelling-controlled release systems”. When these drug delivery systems come into contact with a thermodynamically compatible solvent, relaxation of polymeric chains takes place. Swelling is the macroscopic evidence of this transition. The dissolved drug diffuses into the external receiving medium, crossing the swollen polymeric layer formed around the matrix.

Commercial drug delivery systems for the oral route are manufactured mainly in the dosage form of matrices: they are compounded by a significant amount of drug dispersed in and compressed with a hydrophilic polymer, very often with the addition of soluble or insoluble fillers. the drug release rate appears to be independent of drug solubility at the same loading value. This is due to the swelling and dissolution characteristics of polymer that prevail in determining front movement.

Finally, when the swelling front is no longer active, these systems behave as classical erodible matrices and eventual constant release is due to synchronization of diffusing and eroding front movement. Why we don’t use polyox 2. 2. Preparation of hydrogels Aqueous solutions of 1. 50, 1. 65, 1. 83 and 2. 00 g of PEO, have been prepared by dissolution in 100 ml distilled water.

They are denoted as G-1, G-2, G-3 and G-4, respectively. The aqueous PEO solutions were placed in sealed glass tubes and irradiated in a Gammacell 220, 60Co _-irradiator at room temperature at two different dose rates (0.47 and 6. 1 kGy/h).

Irradiations were carried out up to a total given dose of 50 kGy and % gelation versus dose curves were constructed. About 40 kGy has been determined to be the lowest dose corresponding to maximum gelation (90%) (Savas? and Gu? ven, 2001 in press). After irradiation, hydrogels obtained in long cylindrical shapes were cut into pieces of 3–4 mm thickness. 2. 4. Loading of acti_e substance For the investigation of active substance release behavior of PEO hydrogels prepared in this study, salicylic acid, phthalic acid and resorcinol were used as model substances.

They were selected as representatives of aromatic structures possessing characteristic carbonyl and hydroxyl functional groups. Dry polymeric gels were loaded with active substance by immersion into aqueous solution of respective active substance at 25 °C for 1 day. Preliminary tests showed that 1 day is the minimum time to ensure complete swelling of gel and maximum loading of active substance. Advantages – simple concept, cheap excipients, safe excipients, high drug loading, erodible, reduce possibility of ghost matrices, easy manufacture, different types of release is attainable.

Disadvantages – release of drug dependent on two diffusion processes – water and drug, eroding matrix can complicate the release profile, need for optimal rate-controlling polymers for different actives. Note that different viscosity grades of the HPMC does not significantly affect the drug release kinetics Componenets of hydrophilic matrix delivery systems – Active Drug – Hydrophilic colloids (HPMC) – these swell upon hydration and control drug release.

– Matrix Modifier – modifies diffusional characteristics of the gel layer, usually to either improve hydration of the gel matrix, crosslinking, or modify the gel characteristics to speed up or slow down diffusion. – Solubilizer and/or pH modifier – improve solubility of drug – Compression aid – – Lubricant/glidant – reduce friction and aid compression.

Also reduces sticking to punches or die, and improve flow of the machine (eg mg stearate) Hydrogels are crosslinked hydrophilic polymers capable of imbibing large volumes of water, yet insoluble in water, but swellable when immersed.

Hydrogels are known as good candidates for controlled release formulations for pharmaceutical applications mostly due to their high biocompatibility. In recent years, these polymeric carriers have been extensively considered in sustained and controlled release devices for the delivery of water-soluble drugs PEO used in this study was a commercial product obtained from BDH Chemicals Ltd.

The number average molecular weight of the sample, Mn, is calculated by gel-permeation chromatography as 73 000. What to chose HPMC or Polyox?

HPMC – good compression characteristics, has adequate sweeling properties, and can accommodate high levels of drug loading and considered as non-toxic. [pic] When water penetrates the solid HPMC, it inserts inself into the hydrogen bonds between adjacent polyer chains.

As more water comes between the chains, the forces between the chains diminish and gain rotational freedom and begin to occupy more space- resuling in the swelling of the polyer. The drug diffuses out (zone 2) and release via erosion (zone 3). The HPMC eventually erodes away.

With the polyox – it requires pre-treatment of PEO in water, and the irradiated to commence permenanet cross- linking, and taking up water. This gel is dried, and then the drug is taken up when soaked in a solution of active drug for 1 day. Polyox is what we call a “true hydrogel” – as it does not erode away like the HPMC –ie, there is not change in size. The drug just diffuses out.

This will leave a ghost matrix at the end (poop). It is possible to create biodegradable PEO-based hydrogels via chemical reactions, but it can become very time consuming and complicated.

– I personally don’t know how to make this into a tablet. Anyways, HPMC would be called a “hydrogel”, in more definite terms, because the cross-linking is due to mainly H-bonds, and thus then to erode away – “physical hydrogel would be the more appropriate term. (from one of Majid’s articles)

Polyox on the other hand, when undergoes radiation, makes covalent crosslinks which is very strong, and is called “chemical hydrogels” – and tend not to degrade. Therefore in terms of simplicity, cost, and time, it will be easier to go with HPMC hydrogel. Manufacture Can use either: – Direct Compression,

How it works – after mixing the powder drug and excipients, the powder is directly compressed to form the end product: the tablet. Advantage – fast, simple, no need for costly machines, and quick to do, saving money, no need to worry about stability of product under dry condition.

Disadvantage – need special fillers, and dry binders, flowability may be an issue if the powder is not granulated first. May have difficulty getting high homogeneity and may require a larger number of quality tests. Dry Granulation How it works – after mixing the powders, the mixture is compacted either by slugging, or roller compaction to form granules.

It is broken down by milling, and sieving to find correct sized granules. Advantages- dry, so no need to stability issues, granulation improves compaction, less costly than wet granulation as it takes shorter time, and no need for granulation fluid.

Improves flow properties and compaction Disadvantages – cannot produce different types of types of granules, particles, as with wet granulation such as spherical pellets which can be used in controlled release. Wet Granulation How it works – The powders are mixed thoroughly and a mixer and the granulating liquid is added.

When mixed, and agglomerated, it is sieved, and dried to remove the granulation fluid, mixed with lubricant such as Mg stearate, and then compressed into tablet. Advantages – can form granules binds at different strength, size and shape. Also allows for good flow characteristics, and pellets for controlled release.

Disadvantages – costly equipment, have to use acceptable granulating fluid, and drying – high temperatures may make drug unstable. Very time consuming. In many cases, drug-HPMC mixtures do not have adequate flow characteristics for tableting or direct die filling (Liu et al., 1993).

In general, granulation process is commonly employed to produce HPMC based granules with a high degree of compressibility and good flow characteristics for controlled release HPMC matrix tablets (Liu et al. , 1993; Ebube et al. , 1997b).

As during granulation numerous processing parameters may affect the quality and integrity of controlled release HPMC matrix tablet; the solvents used for wet granulation and coating process such as water, ethanol, isopropyl alcohol and methylene chloride should be carefully selected to assure reproducibility of HPMC based matrix granules or tablets.

Most of all, water is widely utilized as a granulating solvent to prepare HPMC matrix tablet (Liu et al. , 1993; Ebube et al. , 1997b; McConville et al. , 2004). However, wet granulation or polymeric coating with water is not preferable because HPMC has a tendency to form gel and lumps in the presence of water (Liu et al. , 1993; Cao et al. , 2004).

Nonaqueous solvents are also avoided due to their environmental and regulatory issues. Therefore, proper selection of a solvent or cosolvent for wet granulation and coating is very important to establish the quality and reliable release characteristics of HPMC based dosage forms. A mixture of ethanol and water (28%/5% based on total batch weight) as a granulating or coating solvent would be more desirable rather than water only or harmful coating solvent like methylene chloride.

The current monolithic HPMC matrix tablet via wet granulation process was easily produced using a conventional tablet machine A granulation step is sometimes needed to obtain adequate flow properties in CR formulations in which the HPMC polymer level is _20% of the final tablet weight.

The formulation must flow evenly on high-speed tablet equipment to maintain uniform weight and drug content in each tablet. Because cellulose ether polymers are hydrophilic, water addition can make wet granulation challenging. Thus, a dry process that creates uniform powder flow and does not interfere with the final physical characteristics and drug release of the tablet could be useful.

Types of Coating – Film Coating, sugar coating and Press coating, Functional Coating The aim of coating is to improve overall appearance with gloss and colouration, and also to mask any bitter taste that maybe on the table.

Also adds added mechanical strength. Functional Coating may also add pharmaceutical function such as enteric coating- controlled release. It is also possible to coat our HPMC tablet, so that it only exposes a constant amount of surface area so that drug release is constant. However, it may prove a bit hard to do considering that the tablet will swell upon taking in water. It will probably be more trouble that it is worth.

Film coating should be chosen because: – retains original shape – only adds 2-3% mass – able to apply LOGO – Single stage process (for sugar coating, it is multistage) – Takes 1. 5 – 2 hours (for sugar coating, it is over 8 hrs) – Adaptable for controlled release. – Improves shelf life – Can use – HPMC – Masks taste.

How it works – it requires a machine that atomises the coating solution or suspension and spray onto the bed of tablets while the tables are mixing and agitated. Sufficient heat input in the form of drying air to provide enough heat to dry of solvent, leaving the coat on the tablet.

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