CNS antipsychotic formulations

Antipsychotics tend to have a low compliance due to patients usually having reduced competence So we want something with a long duration

Concerta and OROS technology Methylphenidate 3 layers: o Initial release through the coating for a quick loading dose (1) o Water enters through the semipermeable membrane and into the osmotic push layer compartment, which then starts swelling o The swelling causes layer (2) to be pushed out at a constant rate through the precision drilled hole. This layer contains enough drug to keep levels steady through the morning Note: this hole is precision drilled, as it controls the rate of release of the drug from the tablet o Eventually, layer (3) gets pushed out, which causes a massive peak in levels, as attention spans tend to be low in the afternoon o But that layer runs dry soon, which allows the plasma concentrations to fall off to allow the person to sleep Remember: tablet remains intact, tell the patient not to panic if they see it in the toilet Paliperidone (risperidone metabolite, active) ER tablets as INVEGA uses OROS tech as well o Reduces sawtooth profile compared to standard release products

Intramuscular injections Tends to be good when you need to hold someone down and administer it against their will o Works faster too, so they are under control quickly compared to the oral dose Long lasting, so good for non-compliant patients (1-2 inj every month) Stable plasma concentrations, and they cant deliberately overdose

But it comes with problems as well: o Greater risk of EPS with haloperidol injections o Pain at the injection site o Expensive, needs to be sterile o Cant stop therapy early if they develop side effects Risperidone can come as Risperidal o PGLA microspheres, a biodegradable polymer which dissolves and releases drugs slowly over time o Uses an aqueous diluent/vehicle, less pain compared to oily depots Testing drug release for these formulations is tricky, there is no standardised test o Comparison between products and labs is erratic o Cant approve drugs since they cant demonstrate release properties reliably (i.e. prove inter-or intra-batch variability in drug release isnt going to affect treatment) Currently using USP apparatus 4, a flow through cell: o Uses glass beads to hold the drug microparticles in place o Fresh buffer is continuously pushed in, maintains sink conditions

Release rate from microspheres depends on two factors: o Rate of polymer degradation, ideally, we want this to be the rate limiting factor Allows for control of release rate

Glass transition temperature of PGLA is 48 degrees, degradation and rate of release significantly increases above this temperature. Revision: the size distribution of these spheres is varied, the smaller spheres will dissolve quickly, giving quick release to try and start an initial loading dose, the larger ones will release drugs over a longer period of time o Rate of diffusion of the drug away from the site There is a short lag time before full drug release, need to give it some time for the polymers to break down:

Invega sustennatm Paliperdrone palmitate IM injection, its a suspension to be injected A prodrug formulation, need to think of two rate control mechanisms: o Dissolution of paliperdrone palmitate from the solid o Paliperdrone palmitate must then be hydrolysed to its active form (paliperdrone), because the palmitate is actually an ester attached to it In-situ forming implants (ISFIs) As the name suggests, a solid-ish implant forms inside the persons muscle after giving a liquid injection o This witchcraft is achieved by injecting a polymer along with a rapidly dispersing carrier (which keeps the polymer soluble). Therefore, once the injection is given, the concentrations of the carrier will be reduced at the site of injection, causing the polymer to precipitate into a solid implant with drug in it.

The drug can either be dissolved inside the polymer (using NMP solvent) or solid bits of drug dispersed (using DMSO solvent) o The NMP solubilised form causes a very fast release, as the drug is already soluble o The DMSO has a slow, but constant release, as the drug must go through a dissociation step to enter into solution

Misc

Transdermal patches available for selegiline o Bypass first pass metabolism, get more drug in OraSolv dispersible tablets o Saliva causes carbon dioxide bubbles to be released, which causes more saliva release o Quickly disperses drug into solution, allows for rapid absorption compared to conventional release forms

Pastes, gels, creams and ointments

These are semi-solid dosage forms usually used for topical treatments Semi-solids are substances with plastic flow properties o They wont spread out to the shape of the container (i.e. wont move at low shear forces) o They will spread and move easily at higher shear forces (e.g. pushing some out of a tube) We need to classify these things properly because doctors and patients have an expectation each formulation different e.g. an ointment is greasy, a cream isnt as greasy Problem is, the classification hasnt been clear

In general, quick terms: Creams contain water, and they tend to mix well with body fluids. Therefore they arent occlusive (wont feel greasy) o Has at least 2 phases, with oil and water. See below for microstructure Thermogravimetric analysis shows several phases (curves show multiple transitions) o Tends to be based on water or volatile components, has more water compared to ointments Ointments tend not to mix well with body fluids due to non-miscibility with water (i.e. made of substances which wont mix with water, these are the oiligogels). The exception is the macrogol ointments, which are water miscible (the hydrogels), which are less emollient, as they are able to mix with the body fluids o May have more than one phase, see below o Tends to be more stiff (in terms of rheology) compared to creams, but there is some overlap between the two o Tends to have a low portion of water and volatile components, makes it feel more stiff as well Pastes contain a very high portion of solids. They will feel dry and chalky, and will feel stiff to the touch. Good for application to small areas A gel tends to be something with a high portion of water, which is suspended by some kind of gelling agent. o On average, highest amount of water o Can be one or two phases, but needs to be made of a solvent + the gelling agent which holds everything together by weak Vander Waals forces or electrostatic forces between the chains o Thermogravimetric shows only one transition, suggests one phase system o But can be an oligogel, which is a gel consisting of hydrophobic substances only Microstructure Helps us to understand the properties of the semisolids o The consistency especially Miscibility with body fluids: o Ointments tend not to be miscible with body fluids because they contain hydrophobic components, and they generally dont allow water in, which is why they are occlusive o If we see the microstructure for white soft paraffin, its easy to see why it cant let water in:

The chains of the paraffin will not accommodate water, as there are no hydrophilic regions to be found o Note: according to Walker, white soft paraffin can also be regarded as a lipophilic gel, as it fits the description One or more phases (two are seen here, the crystalline and amorphous) Made up of more than 1 component (made up of several different hydrocarbons) Coherent network of chains and lamellae to form a continuous mass Network is held together by Vander Waals forces Immobilises liquids (e.g. paraffin) within If we compared this to creams, its vastly different, as creams tend to contain surfactants to bind to water in a specific manner to allow water to be incorporated into the structure:

This o/w emulsion diagram shows that there are at least 4 phases present o A. is the water (represented as dashes) being incorporated between the lamellae (intra-lamellar water)

This even incorporation of water into the structure is important, as it is what allows the cream to be miscible with water. o B. shows a crystalline surfactant phase with hydrate water (i.e. the surfactants are organised regularly, and the water isnt organised between them just yet, so it shows this cream isnt fully hydrated yet) o C. shows a dispersed oil phase (the wavy lines) which is kept dispersed by the surfactants, it keeps the oil separate from the water phase (this is an oil in water cream after all) o D. shows the water bulk phase, notice how the water molecules (dashes) are not organised Since we were able to pick out 4 different phases, this is why thermogravimetric analysis showed many different phases Note: w/o has a similar thing going on:

There are three phases present (this doesnt have water added yet) A crystalline surfactant phase (seen a long ribbons) Note: the water would be incorporated between these chains of surfactants as intra-lamellar water, which means these w/o creams are able to ACCOMMODATE water (makes them miscible with body fluids) The water would make up the 4th phase once its added A crystalline soft paraffin phase (the solid wavy bits in the middle) An amorphous soft paraffin phase (the spread out wavy bits) IN SUMMARY OF THE ABOVE: o Can incorporate water into microstructure = miscible with body fluids on the skin = doesnt feel greasy o Cant incorporate water into microstructure = NOT miscible with body fluids on the skin = feels greasy (occlusive) Lastly, a macrogol ointment is composed of long chains (macrogol 4000) interspersed with shorter chains (macrogol 300) o Without the shorter chains, the long chains would just be bunched up tight next to each other with significant Vander Waals forces, this would make it feel like a very stiff substance (its actually solid) o But since there are short chains, they force the long chains apart, reducing the density of the interactions (i.e. causes swelling of the crystalline structure), allowing

the chains to flow past each other easily, making it behave like a semi-solid, instead of a solid. It is a single phase system, because the macrogol 300 chains dont separate out, instead they mesh in quite well with the long 4000 chains