By N. Zuben. Coastal Carolina University.
In poor coun- tries buy cheap astelin line, where medicines rank second only to food as a household expense (Cameron et al buy astelin 10 ml visa. When government or donors supply medicines quality astelin 10 ml, they shoulder the added costs of falsifed and substandard drugs. Chapter 4 describes the pressure on procurement agencies to fll drug orders for the lowest prices, a false frugality that can cause the wasting of an entire medicines budget on drugs with insuffcient active ingredients. The costs only grow when expensive drugs are targeted or when they are Copyright © National Academy of Sciences. It is not yet clear how much patients and insurance companies paid for falsifed Avastin during the 2012 crisis, but the Wall Street Journal found that the fake product sold for almost $2,000 per vial (Weaver and Whalen, 2012). Drug resistance will increase costs to the health system, and not only because of increased clinical attention. Already the cheapest, oldest classes of anti-infective drugs are becoming useless. Society must bear the expense of new drug develop- ment, an ever-increasing cost (see Figure 2-3), because resistant pathogens require treatment with more complex drugs. Aside from the direct fnancial costs of treatment, there are opportunity costs incurred to patients who miss work for additional doctors’ visits or become too sick to work. Chapter 3 will explain that the burden of falsi- fed and substandard medicines is borne mostly by the poor in South and Southeast Asia and sub-Saharan Africa. Transport costs and opportunity costs are a known obstacle to health care for these patients (Whitty et al. Customers at gray pharmaceutical markets, including fea markets, Copyright © National Academy of Sciences. For example, participants at the São Paulo site visit for this study explained that although medicines are free through the public health system in Brazil, miners and other daily-wage workers circumvent this system. They continue working and self-treat with medicines of dubious quality from the gray market. In Brazil, as in many parts of the world, falsifed and substandard medicines extract the highest costs from those who can afford the least. Scientists and policy makers in developing countries are aware of the toll falsifed and substandard drugs take on their health systems. Patients may begin to distrust modern pharmacies after experiences with falsifed and substandard drugs. In Ugandan villages, the proportion of positive responses to the question “Do you expect that the antimalarial medicines sold by the nearest drug shop are fake? As well as having accurate doubts about individual pharmacies, con- sumers in places where fake drugs circulate have reason to lose faith in the public health system. A recent systematic review suggests that patients across a range of developing countries already have poor perceptions of the health system, especially the technical competence and clinical skills of the staff and the availability of medicines (Berendes et al. Poor-quality medicines stand to damage the perception of the health system even more. Qualitative research in China suggests that patients view the loosely regu- lated private health care system poorly, seeing it as rife with “fake doctors” and “fake drugs” (Lim et al. Participants consistently attributed this poor confdence to unplanned pregnancies following a 1998 lapse in the quality of oral contraceptives (Associated Press, 1998; Goering, 1998). Anvisa, the Brazilian drugs regulatory authority, was created in response to this and other medicine quality problems (Csillag, 1998). They are evidence, however, that fake medicine can do long-term damage to the reputation of the health system. Social and Developmental Costs In a larger sense, trade in falsifed and substandard medicines under- mines not just the health system but all public institutions. Falsifed medicines are often the business of criminal car- tels, including the Camorra crime group in Naples, the Russian mafa, and Latin American drug cartels, and terrorist organizations, such as Al-Qaeda and Hezbollah (Findlay, 2011). Fake medicines generate income for criminals, and only the weakest evidence, if any, ties them to their crime. Acute cases of medicine poisoning can elicit public outcry, but more often bad drugs go unnoticed, blending in with lawful business. Victims of falsifed and substandard drugs usually do not even know they are victims and are therefore deprived of their right to redress. In many parts of the world, falsifed and substandard medicines further erode the already weak political infrastructure that allows them to circulate, part of a vicious cycle of poverty and crime. Countering the Problem of Falsified and Substandard Drugs 75 Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 76 Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 77 Copyright © National Academy of Sciences. Diagnosing renal failure due to diethylene glycol in children in a resource-constrained setting. High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in Western Cambodia. Distribution of causes of maternal mortality among different socio-demographic groups in Ghana: A descriptive study. Quality of private and public ambu- latory health care in low and middle income countries: Systematic review of comparative studies. False resistance to antiparasitic drugs: Causes from shelf availability to patient compliance. Medicines prices, availability, and affordability in 36 developing and middle-income countries: A secondary analysis. Fatal poisoning among young children from diethylene glycol-contaminated acetaminophen. In vitro assessment of qual- ity control parameters of some commercially available generics of amlodipine besylate in Nigerian drug market. A 6-year (2004-2009) review of maternal mortality at the eastern regional hospital, Koforidua, Ghana. Vaccine supply chains need to be better funded and strengthened, or lives will be at risk. Epidemic of plasmodium falciparum malaria involving substandard antimalarial drugs, Pakistan, 2003. Are counterfeit or substandard anti-infective products the cause of treatment failure in Papua New Guinea? Institute of legal medicine advances in review of pending cases: 219 are killed by syrup. Burden of disease caused by streptococcus pneumoniae in children younger than 5 years: Global estimates. Comparative assessment of the qual- ity control measurements of multisource amlodipine tablets marketed in Nigeria. Epidemiological survey of mithicillin resistant Staphylococcus aureus in the community and hospital, Gannavaram, Andhra Pradesh, South India.
Efforts to guarantee good schooling for children order cheapest astelin, possibly through boarding schools or scholarships buy astelin 10 ml with amex, could remove a barrier to rural service (Rao et al order astelin 10 ml with mastercard. Health workers also have concerns about quality of life and physical hardships in rural posts (Rao et al. Subsidized housing or provi- sion of modern living quarters could help in places where this is a common concern. It is also possible to recruit pharmacy technicians and pharmacy assistants from underserved communities. Training students from rural and remote areas is a known way to reduce attrition in these posts (Rabinowitz et al. The Australian Rural and Remote Pharmacy program has successfully increased service to rural and isolated communities, in part through giving scholarships to students from rural backgrounds (see Box 5-4). Internet Pharmacies in Middle- and High-Income Countries Disorganized medicines retail is not confned to developing countries. The previous section describes the large gray market for medicines in ba- zaars and unlicensed drug shops in low- and middle-income countries. The internet serves the same purpose, but mostly in middle- and high-income countries. Illegitimate internet pharmacies are similar to unlicensed drug shops both in the quality of the products they stock, which is poor, and in the lack of offcial oversight of their operations (Crawford, 2003). And, because the internet facilitates easy international sales, online drug stores have spread the problem of falsifed and substandard drugs “from small, unproftable, markets in developing nations to the [drug] industry’s most lucrative markets” (Lybecker, 2007, p. The program aims to improve access to pharmacy services in rural or remote regions and includes a variety of initiatives to improve recruitment and retention of rural pharmacists. The program also increases pharmacy students’ exposure to rural work during their training. Australian pharmacy students work in com- munity or hospital pharmacies as part of their studies. The program also supports students from rural backgrounds to pursue pharmacy degrees. Another successful initiative to improve retention is the program’s emer- gency locum service. Figure 5-6 shows the geographic breakdown of the 30 countries that have legislation on the operation of internet pharmacies. A few countries have an accreditation process for their own internet pharmacies, but internet commerce is transnational. Perhaps concern about the practicality of enforcing laws against internet drug sales prevents countries from passing them. It may also seem futile to ask internet drug sellers to observe the same stan- dards registered pharmacies do, such as requiring doctor’s prescription for controlled medicines, when “national rules banning the sale of drugs with- out a prescription can be easily overcome” (Levaggi et al. Just as often, restrictions and quality controls for online pharmacies are not, in fact, violated because many internet pharmacies operate out of countries that have no such restrictions. Although regulatory agencies can ask foreign governments to close online drug stores, it is diffcult to prevent them from reopening at a different address (Ivanitskaya et al. Because the products are sent through courier or postal services, customs and border offcers may also stop the imported drugs at the port of entry (Ivanitskaya et al. The Attraction of Internet Pharmacies Some of the more reputable-looking internet drug sellers keep up the pretense of having patients complete a health questionnaire before buying drugs, but many do not (Ivanitskaya et al. Bostwick and Lineberry proposed four main categories of customers at internet pharmacies: bargain hunters, the poor or elderly, the “life- style libertines” who prefer to self-prescribe, and drug addicts (Baert and De Spiegeleer, 2010; Bostwick and Lineberry, 2007). Of these groups, ad- dicts are the least likely to purchase prescription drugs online (Inciardi et al. Internet drug stores cater to people who like to buy drugs with- out, or even against, a physician’s advice (Levaggi et al. Table 5-3 shows other perceived advantages and disadvantages of online pharmacies. Other online shoppers seem motivated by a belief, sometimes a mis- taken one, that internet pharmacies sell cheaper drugs. On average, the investigators paid more for the drugs that never arrived than for those that arrived (€0. Investigators cited other hidden costs, including ship- ping and customs fees, as well as the cost of time spent waiting for the slow transactions to process (Levaggi et al. More importantly, of the 13 pharmacies that flled orders, only two were not of substandard quality (Levaggi et al. They criticized the false economy of online drug sellers in part because the products they bought sell for less in Italian regulated, storefront pharmacies (Levaggi et al. A 2001 study of Parkinson’s disease medications found on- line drug stores offered substantial savings off U. A Forbes magazine contributor explained, “My wife needs the meds to stave off a recurrence of cancer, so avoiding [online pharmacies] is not an option” (Wasik, 2012). The risks of online purchases are, especially in the United States, inextricable from larger questions of affordable drug pricing (Financial Times, 2012). Every year more Americans, and others accustomed to using the internet for bargain shopping, import “incremental amounts” of medicines to their countries though gray market internet purchases (Laven, 2006; Shepherd, 2007b). Distinguishing Rogue Pharmacies from Legitimate Ones In late September 2012, Interpol, an intergovernmental organization for police cooperation, organized an international raid of online pharmacies A GlaxoSmithKline ad campaign about the dangers of online pharmacies purporting to sell Canadian medicines. The operation, known as Pangea V, is part of Interpol’s enforcement against pharmaceutical crime. Although there is value to shutting down criminal online drug stores, in the longer term, it may be more helpful to recognize the e-commerce division of le- gitimate pharmacies. The challenge of recognizing legitimate online pharmacies As Table 5-3 mentions, online pharmacies can be a boon to people who live in remote areas or who cannot manage in-person shopping. These consumers need reliable advice on how to navigate the confusing internet marketplace. There are many reputable pharmacies with licensed e-commerce divisions, but identifying them can be diffcult. Both the United States and Europe have accreditation programs for legitimate online pharmacies. The program also recognizes some independent internet businesses such as Medco’s Express Scripts (Medco Health, 2012). In addition to patient education materials, the agency’s website will link patients to na- tional regulatory authorities’ websites that will maintain a list of authorized online pharmacies. The authorized pharmacies will in turn post an accredi- tation logo that links back to the regulatory agencies’ website (Cockburn, 2011). The committee agrees that indepen- dent accreditation is a useful tool for consumers trying to make sense of the chaotic world of online medicine retail. A 2008 study found that about 20 percent of online drug stores displayed an approval of a regulatory or accrediting agency, but about 80 percent of these approvals were phony (Mayor, 2008).
Pharmacodynamics Zonisamide’s precise mechanism of action is unknown purchase astelin with mastercard, but it’s be- lieved to involve stabilization of neuronal membranes and sup- pression of neuronal hypersensitivity order 10 ml astelin otc. Adverse reactions to sulfonamides Common adverse effects of zonisamide in- More serious adverse effects associated clude: with zonisamide use include: • somnolence • Stevens-Johnson syndrome • dizziness • toxic epidermal necrolysis • confusion • psychosis • anorexia • aplastic anemia • nausea • agranulocytosis generic astelin 10 ml mastercard. Low doses should be tration with meals may decrease the incidence initiated in elderly patients because of the pos- of these adverse effects. Drug interactions • Drugs that induce liver enzymes, such as phenytoin, carba- mazepine, and phenobarbital, increase the metabolism and de- crease the half-life of zonisamide. It’s used as adjunctive therapy to treat certain types of partial and myoclonic seizures. Levetiracetam isn’t exten- sively metabolized; any metabolites that are produced aren’t ac- Adverse tive. The major metabolic pathway is enzymatic hydrolysis, and reactions to metabolism doesn’t depend on any hepatic cytochrome P450 levetiracetam isoenzymes. The half-life is about 8 hours and is unaffected by dose, route of ad- Common adverse reac- ministration, or repeated administration. The drug’s • fatigue antiepileptic effect doesn’t appear to involve known mechanisms relating to inhibitory and excitatory neurotransmission. Pharmacotherapeutics Less common ad- Levetiracetam has several indications for us, including: verse reactions include: • adjunctive therapy for epilepsy in adults and children older than • depression age 4 • pharyngitis • adjunctive treatment for myoclonic seizures in adults and chil- • conjunctivitis dren older than age 12 • mood swings. Drug interactions Sensitivity to Levetiracetam has no known major drug interactions. Antimigraine drugs Migraine is one of the most common primary headache disorders, affecting an estimated 24 million people in the United States. An episodic disorder, mi- graine produces a unilateral pain that’s commonly de- scribed as pounding, pulsating, or throbbing. Other common symptoms are sensitivity to light or sound, nausea, vomiting, constipation, and diarrhea. Researchers believe that migraine symptoms are caused by cranial vasodilation or the release of va- soactive and proinflammatory substances from nerves in an activated trigeminal system. How can you Choice of therapy depends on the severity, duration, and frequen- tell if it’s a cy of the headaches; on the degree of disability that the headache migraine or a head- creates in the patient; and on patient characteristics. They include: • almotriptan • eletriptan • frovatriptan • naratriptan • rizatriptan • sumatriptan • zolmitriptan. Rizatriptan, sumatrip- Sound-alikes: tan, and zolmitriptan have a half-life of approximately 2 hours; al- motriptan and eletriptan have a half-life of 3 to 4 hours; naratrip- Sumatriptan tan has a half-life of about 6 hours; and frovatriptan has the and zolmitriptan longest half-life (25 hours) and the most delayed onset of action. Don’t confuse the Triptan tablets sound-alike drugs suma- All of the triptans are available in an oral form. Zolmitrip- Both drugs are used to tan and sumatriptan are available in intransal forms. The injectable form but recommended dos- of sumatriptan has the most rapid onset of action of all the trip- es are significantly dif- tans. A patient experiencing nau- include: sea and vomiting may prefer injectable or intranasal sumatriptan. However, triptans with a • nasal and throat dis- longer half-life have a delayed onset of effect. Two newer triptans, comfort almotriptan and eletriptan, have a rapid onset and an intermediate • vision disturbances half-life. If a triptan tients with cerebrovascular syndromes, such is used in this setting, the first dose should be as strokes or transient ischemic attacks, or for administered in a doctor’s office or other med- patients with peripheral vascular disease, in- ically staffed and equipped facility. Triptans shouldn’t be given to patients tans and those who have risk factors should with uncontrolled hypertension or with hemi- undergo periodic cardiac evaluation. Some common preparations used for migraine include: • ergotamine, available in sublingual and oral tablets and supposi- tories (combined with caffeine) • dihydroergotamine, available in injectable and intranasal forms. Peak plasma concentration, following subcutaneous injection, is within 45 minutes, and 90% of the dose is plasma protein-bound. Ergota- mine is metabolized in the liver, and 90% of the metabolites are ex- creted in bile; traces of unchanged drug are excreted in urine. Pharmacodynamics Ergotamine-derivative antimigraine effects are believed to be due to blockade of neurogenic inflammation. They also act as partial agonists or antagonists at serotonin, dopaminergic, and alpha- adrenergic receptors depending on their site. Ergotamine prepara- tions often need to be prescribed with antiemetic preparations when used for migraine. Dihydroergotamine, a hydrogenated form of ergotamine, dif- fers mainly in degree of activity. It has less vasoconstrictive action than ergotamine and much less emetic potential. Pharmacotherapeutics Ergotamine preparations are used to prevent or treat vascular headaches, such as migraine, migraine variant, and cluster headaches. Dihydroergotamine is used when rapid control of mi- graine is desired or when other routes are undesirable. Drug interactions • Propranolol and other beta-adrenergic blocking drugs block the natural pathway for vasodilation in patients receiving ergotamine preparations, resulting in excessive vasoconstriction and cold ex- tremities. Adverse reactions to ergotamine derivatives Adverse effects of ergotamine derivatives include: • nausea and vomiting • numbness • tingling • muscle pain • leg weakness • itching. Prolonged administration of ergotamine derivatives may result in gangrene and rebound headaches. Contraindications to the use of er- Vasoconstrictors gotamine preparations include coronary, cerebral, or peripheral vascu- may increase the lar disease; hypertension; and liver or kidney disease. Don’t give any ergotamine prepa- rations and triptans within 24 hours of each other. A 15-year-old patient has a tonic-clonic seizure disorder and is prescribed phenytoin. Which potential adverse reaction makes it unlikely that valproate will be prescribed for this patient? When given to children and patients taking other an- ticonvulsants, valproate carries a risk of fatal liver toxicity. A 48-year-old patient has been prescribed trihexyphenidyl for her Parkinson’s disease. Which antiparkinsonian drug is associated with the on-off phenomenon and the wearing-off effect? Levodopa is associated with the on-off phenomenon (sharp fluctuations in symptoms) and the wearing-off effect (shorter duration of the drug’s effects) in patients who have taken the drug for many years. Some doctors believe the drug should be given in lower doses or started later in the course of the disorder.
M anufacturing (Direct com pression) M ix all com ponents buy astelin no prescription, pass through a sieve and press with m edium com pression force discount astelin 10 ml otc. M anufacturing (Direct com pression) M ix all com ponents and press with a low com pression force purchase cheap astelin line. Rem ark These tablets could be com m ercialized in Europe as dietary food because all com ponents are allowed for this application. M anufacturing Dissolve betam ethasone valerate in the m ixture of Lutrol E 400 and M iglyol 812. Physical stability No change of appearance or crystallization were observed during 6 weeks at 45 °C. Rem ark Perhaps a certain am ount of propylene glycol could be substituted by water. Physical stability No change or appearance or crystallization were observed during 6 weeks at 45 °C. M anufacturing (Direct com pression) M ix all com ponents, pass through a sieve and press with m edium com pression force. Rem ark If the bran is not m illed, the hardness of tablet is higher but the content uniform ity is less. These tablets could be com m ercialized in Europe as dietary food because all com ponents are allowed for this application. M anufacturing Dissolve the preservative in hot water, cool, dissolve Kollidon 25, add chloram phenicol and stir until a clear solution is obtained. Rem ark To prevent of discolouration of Kollidon in the solution during storage 0. M anufacturing M ix com ponents I at 70°C to obtain a clear solution and cool to about 40 °C. Physical Stability After 3 weeks at room tem perature and at 45 °C no change of appea- rance and viscosity was observed. M anufacturing Dissolve chlorhexidin diacetate in propylene glycol at >70 °C, stir well and add slowly Lutrol F 127 and water. M anufacturing (Direct com pression) M ix all com ponents in a turbula m ixer and press to tablets with a com pression force of 20 kN. Rem ark If the content uniform ity does not m eet the requirem ents it would be recom m ended to prepare a prem ix of clenbuterol hydrochloride with a sm all part of the Ludipress before m ixing with the other com ponents of the tabletting m ixture. M anufacturing (Direct com pression) M ix all com ponents, sieve and press with low com pression force. Physical stability No change of appearance or crystallization were observed during 6 weeks at 45 °C. Rem ark The dosage m ay be increased to 2000 m g crospovidone by increasing the tablet weight to 3200 m g. Rem ark The dosage m ay be increased to 2000 m g Crospovidone by increasing the tablet weight to 2600 m g. Rem ark If the content uniform ity does not m eet the requirem ents it would be recom m ended to prepare a prem ix of the active ingredient with a sm all part of the Ludipress or with lactose m onohydrate before m ixing with the other com ponents of the form ulation. M anufacturing Dissolve dexpanthenol and Lutrol E 400 in water, add liquid paraffin and stir heating to 60 – 70°C. Properties of the solution A clear colourless solution of very low viscosity was obtained. M anufacturing Dissolve Lutrol F 127 in water at 4 – 6 °C (or at >70 °C) and m ix with the solution of diclofenac sodium in propylene glycol. M anufacturing Dissolve diclofenac sodium in propylene glycol, add the m ixture of water and M iglyol 812. M anufacturing Dissolve diclofenac sodium in the aqueous solution of the auxiliaries. Physical stability There was no crystallisation after the storage of 2 weeks at 6 °C. M anufacturing (Direct com pression) M ix all com ponents, pass through a sieve and press with low com pres- sion force. M anufacturing (Direct com pression) M ix all com ponents, sieve and press with low com pression force. Rem ark To enhance the flowability of the tabletting m ixture the am ount of Aerosil 200 could be increased. Rem ark If the content uniform ity does not m eet the requirem ents it would be recom m ended to prepare a prem ix of the active ingredient with a sm all part of the Ludipress or with lactose m onohydrate before m ixing with the other com ponents of the form ulation. The sterilisation can be m ade by aseptic filtration or by heating (120 °C, 20 m in). Rem ark To prevent of discolouration of Kollidon in the solution during storage 0. Rem ark These tablets could be com m ercialized in Europe as dietary food because all com ponents are allowed for this application. Influence of the com pression force on the physical tablet properties (Form ulation No. Rem ark The flowability of the tabletting m ixture should be increased by higher am ounts of Ludipress or/and Aerosil 200. M anufacturing Dissolve heparin sodium in water, add Lutrol E 400 and liquid paraffin, stir and cool to 6 °C. Physical stability No change of appearance or crystallization were observed during 6 weeks at 45 °C. Das für die Herstellung verwendete W asser soll vor Gebrauch frisch aufgekocht werden. Rem ark The function of isopropyl m yristate is the reduction of the adhesive properties of Lutrol F 127. Properties of the suspension The redispersibility of the suspension is very easy after 14 days at room tem perature. Chem ical stability Lutrol F 127 (= Pluronic® F 127) stabilizes indom ethacin against hydro- lisis as shown in the following publication sum m ary: Hydrolysis of Indom ethacin in Pluronic F 127 Gels Tom ida H. The degradation of indom ethacin followed 1st order kinetics, with linear plots of the 1st order rate constant vs. M anufacturing M ix the com ponents for about 10 m in and fill in hard gelatin capsules to obtain 160 m g indom ethacin in each capsule. Physical stability (20–25°C) Storage tim e Hardness Disintegration Friability 6 M onths 70 N <1 m in 0. Adm inistration • Instant granules in sachets: Suspend 2 g (= 1 sachet) in a glass of water (= 800 m g M agaldrate) • Dry syrup: Fill the flask with drinking water until the m ark of 100 m l and shake well. M anufacturing Dissolve or suspend all the solids in water under aseptic conditions. Properties of the suspension – W hite hom ogeneous suspension practically without sedim entation during 24 hours. W hen the Lutrol F 127 is com pletely dissolved suspend M ebendazole in the solution. Properties of the suspension After one day of storage at room tem perature no sedim entation could be observed. After som e weeks of storage at room tem perature som e sedim entation occurred but the redispersibility was very easy.
In another vessel astelin 10 ml lowest price, prepare a solution of items 13–16 heated to 75°C with stirring cheap 10 ml astelin with visa. Atropine Opthalmic Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 1 purchase astelin 10 ml without prescription. In a separate vessel, dissolve item 1 in 200 mL of water for injection and add to step 1 under 1. Formulations of Semisolid Drugs 105 Azelaic Acid Cream and Gel Azelaic acid cream 20% contains azelaic acid, a naturally in usual concentrations in 60–70 parts of water. Chemical name: 1,7-heptanedi- polysorbate 80 is added and homogenized while being carboxylic acid. The solution that is produced ents: cetearyl octanoate, glycerin, glyceryl stearate, cet- is stirred into the preemulsion and homogenized. Sodium hydroxide is used to neturalize the car- Benzoic acid is present as a preservative. It has a potency of not less than 6000 polymyxin of bacitracin, a mixture of related cyclic polypeptides B units per milligram, calculated on an anhydrous basis. It has a potency of not less than 40 bacitracin units equal to 10,000 polymyxin B units; inactives: white pet- per milligram. After cooling the oleaginous phase to about 55°C, the triacetin solution is added to the ole- 1. Mixing should be pylene glycol stearate are melted together by of sufﬁcient intensity to disperse the triacetin heating to 75°–85°C, and mixed, thus creating ﬁnely and uniformly. Base Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 10. After cooling the oleaginous phase to about 45°C, the triacetin is added to the oleaginous phase while mixing. Mixing should be of suf- ﬁcient intensity to disperse the triacetin ﬁnely and uniformly. Formulations of Semisolid Drugs 107 Base Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 5. To make the oleaginous phase, white petrola- perse the triacetin ﬁnely and uniformly. Mixing is continued while cooling the ointment crystalline wax are melted at 75°–85°C. After cooing the oleaginous phase to about 55°C, the triacetin is Base Cream for Extemporaneous Preparations Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 7. Heat items 7 and 8 until the active ingredient is dissolved, mix with aqueous solution, and 1. Heat a mixture of items 1–5 and the water sep- continue to stir during cooling to room temper- arately to about 80°C. In a suitable vessel, charge liquid parafﬁn, mixture to cool gradually to room temperature. The gel is a nonsterile, low-bioburden, preserved, let-derived growth factor for topical administration. Each gram of polypeptide chains that are bound together by disulﬁde gel contains 100 µg of becaplermin. Formulations of Semisolid Drugs 109 Benzalkonium Chloride and Zinc Oxide Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 0. Adjust the turbo-mixer of the steam-jacketed tank containing the aqueous phase to maximum 1. Gen- eted tank with vacuum with high-speed agitator erate as much vacuum as possible, and maintain and an adjustable slow-speed anchor type with it for the rest of the process. If necessary, mill zinc oxide in a Fitz mill or temperature decrease (down to 60°C). Stop similar impact-forward, maximum-speed mill, turbo-mixer and put the anchor-type agitator at ﬁtted with a 250-µm aperture screen. Continue to mix until the perfume is completely zinc oxide in solution of stepabove. Dissolve benzalkonium chloride and glycerin in solution maintain temperature at 75°C. In a separate steam jacketed tank, add Polawax, cetostearyl alcohol, acetylated lanolin, oil-neutral vegetable triglycerides mixture, and propylpa- raben, and carefully melt at 70°C. Benzocaine Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 180. Formulations of Semisolid Drugs 111 Benzoyl Peroxide and Alpha-Bisabolol Gel Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 2. Benzoyl Peroxide Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/1000 Tablets (g) 460. Sift carbomer 940 into vortex in water; when gel, allow 15 minutes of mixing to complete completely dispersed, sift in item 3. Hydrate carbopol and permulen in warm water, water (item 8) and add to the emulsion. Formulations of Semisolid Drugs 113 Benzoyl Peroxide Lotion The cleansing lotions contain benzoyl peroxide 4% and magnesium aluminum silicate, propylene glycol, sodium 8%, respectively, in a lathering vehicle containing puriﬁed hydroxide, sodium lauryl sulfoacetate, and sodium octoxy- water, cetyl alcohol, citric acid, dimethyl isosorbide, docu- nol -2 ethane sulfonate. Betamethasone and Cinchocaine Suppositories Bill of Materials Scale (mg/suppository) Item Material Name Quantity/1000 Suppositories (g) 1. Betamethasone and Salicylic Acid Lotion Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 0. Add 20% of item 7 in a separate vessel and add sel and slowly add item 4 with vigorous mixing; and dissolve item 2 into it. Use item 7 to rinse solve item 1 in a separate vessel and then add all vessels and add rinsings. Formulations of Semisolid Drugs 115 Betamethasone Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 70. Heat items 7 and 8 until the active ingredient is dissolved, mix with above mixture, and con- 1. Heat a mixture of items 1–5 and item 6 sepa- tinue to stir to cool to room temperature. After cooling the oleaginous phase to about 55°C, the tiacetin solution is added while mix- 1. The betamethasone dipropionate and citric acid ing to make a homogenous dispersion. Mixing are dissolved in the triacetin with mixing and should be of sufﬁcient intensity to disperse the heat to 35°C if needed. Mixing is continued while cooling at room tem- stearate, and mineral oil are melted together by perature. Betamethasone Gel Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 1. Prepare the solution of items 1–3 at room tem- perature and solution of items 4 and 5 at about 6°C (or at >70°C). Formulations of Semisolid Drugs 117 Betamethasone Opthalmic Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 1. In a separate vessel, dissolve item 1 in 200 mL of water for injection and add to step 1 under 1.
The less politicized local decision concerning a patient’s access to drugs through compassionate use programs in Europe ironically may be fostering uncertainty for frms developing and advancing new pharmaceuticals order astelin 10 ml amex. Personalized Medicine The concept of consumer oriented or personalized medicine has attracted wide attention in recent years order astelin 10 ml with amex. Regulators in both the United States and in Europe are at present seeking to identify and validate biological markers that can serve as surrogate measures for clinical outcomes purchase astelin 10 ml amex. To date, surrogate endpoints are proving contentious, with relatively little international agreement on which measures to use and how to prove that they correspond rigorously to actual health outcomes. While the area is in fux at present and likely to change in coming years, certain trends have emerged. With a cost that can reach up to $100,000 per year, Avastin has raised some concern in the United States; its use in Europe is even more contested. National Institute for Clinical Excellence terminated the review of Avastin in June 2008, effectively making it unavailable to women with breast cancer through the National Health Service. While it has been compared to the Critical Path initiative, it is likely to spend far more to support research in areas such as brain disorders and metabolic disease 43 Gina Kolata and Andrew Pollack, “Costly Cancer Drug Offers Hope, but Also a Dilemma,” New York Times (6 July 2008). Hamermesh, “Realizing the Promise of Personalized Medicine,” Harvard Business Review (October 2007), 109-117, cite at 115. In Germany, for example, the Bundesinstitut fur Arzneimittel- und Medizinprodukte (BfArM) has convened several expert assessments and conferences. At a meeting in June 007, BfArM put the onus on industry and academic researchers to change the design of clinical trials: To date, genetic biomarkers have rarely been incorporated in well-controlled late phases of clinical trials for the purpose of a proactive patient selection or patient stratifcation. Application of pharmacogenetics-based diagnostics in therapeutic decisions would be facilitated if pharmacogenetic analyses were already included in the clinical studies during the development of drugs, but currently this diagnostic approach is still far from being applied in general clinical practice. Third, at a broad conceptual level, fnding a ft between protection of “the patient” and providing information to “consumers” is being conceptualized differently in the United States and Europe. Senate Majority Leader William Frist described a fctional patient and the overall healthcare system in the year 015 in a manner that succinctly captured a trend in the United States of envisioning a personalized therapeutic approach. Interviewed by the journal Personalized Medicine, Dolores Ibarreta of the European Commission Joint Research Center, Institute for Prospective Technological Studies, explained: In the specifc context of personalized medicine, we are looking at barriers for development and clinical implementation in Europe. Frist, “Health Care in the 1st Century,” New England Journal of Medicine 352 (2005), 267-272. Interestingly, the tensions emerging in the United States between making health care responsive to consumers while protecting patients and ensuring they have treatment and care are notably less pronounced in Europe. Conclusion: The Interface of Innovation and Regulation Since 1980 and at a rate that accelerated in the 1990s, the United States became the leading worldwide location for pharmaceutical research, clinical testing, and marketing. The “pharmacy to the world,” once located in Germany, Switzerland, or France, today is found in the United States. Studies of the industry have attributed this sustained competitive advantage to a variety of factors, including U. Government regulation of the pharmaceutical market is revealing a country’s concept of innovation at a specifc historical moment; intriguingly, regulations also shed light on enduring cultural differences between nations. Historically, legislative interventions in the United States were predicated on the notion that patients must be protected by the state from the worst ravages of free-market capitalism. In the 1980s and 1990s, however, patients represented by disease-based organizations agitated for greater access to drugs and speedier approvals. At the same time, critics warned that the country’s competitive standing depended on the pharmaceutical and biotech sectors. Regulation of pharmaceuticals in the United States has followed an overall progression from medical profession to the state to a new consumer/patient oversight model. In Germany, by contrast, the medical profession exercised a near-monopoly over constructions of “the patient” and drug laws codifed existing power-sharing arrangements. Instead of the state claiming authority over pre-market testing, it acted as one member of a network overseeing pharmaceutical drugs. A fexible boundary between testing and market was predicated on informal trial protocols, a structured system for collecting reports of adverse reactions, and compromises among organized interests and government offcials. The drug approval process thus only rarely became a signifcant site for debates over national competitiveness or industry innovation. Nevertheless, Germany too has seen different waves of regulatory style, from physicians to a networked approach that incorporates the state, select disease-based organizations, and the medical profession. The comparative perspectives developed in this chapter suggest that despite recent convergences in government efforts to stimulate and steer innovation, for example through support for small biotech ventures, national regulatory differences infuence the competitive status of the pharmaceutical sector. In contrast to the argument that it is German and European healthcare cost containment that has undermined its domestic pharmaceutical industry, this chapter suggests instead that regulation also plays a role in the success and failure of industry. In fact, the emergence of a consumer/patient regulatory mode in the United States has driven increased use of prescription drugs. While this comes at high fnancial cost and stress on government regulators, it offers the benefts of avoiding painful cost vs. At the same time, the consumer mode that has emerged in the United States has proven easy to manipulate for industry, as in the cases of corporate-fnanced organizations claiming to be self-organized by patients. A combination of public attention to drug prices, health concerns from product withdrawals due to adverse reactions, and criticisms of the failure to deliver medicines to patients in developing countries pose signifcant challenges to industry and regulators. Research on the interplay of pharmaceutical innovation and regulation presented here suggests that signifcant change in the blockbuster model followed by most pharmaceutical companies may not happen as quickly as critics would like. An open question is whether the current “pharmacy to the world” of the United States may soon loose ground to competitors from developing countries. As Indian and Chinese frms that started in the generics business integrate upstream into the invention and testing of new molecules, they may become the next generation of competitors to the current top-ranking frms. Finally, the emergence of a consumer model of regulation poses a number of critical unresolved questions about the longer-term role of government, industry, the medical profession, and citizens. The era of paternalistic medicine has passed, but the notion that patients can act as consumers and make appropriate decisions concerning medical treatment poses countervailing risks of its own. A better accommodation among key players needs to be struck to foster safe use of pharmaceuticals. The precise form of this accommodation will necessarily vary from one country to the next, which holds out the possibility for additional policy learning from future cross-national comparisons. In the biomedical model, medication is defned as a substance that acts on the condition of a living organism. In many other models it is regarded as a mediator of symbolic relationships linking people to their environment. The complexity of these relationships indicates the extent to which – over the course of their interactions – social actors (industry representatives, physicians, pharmacists, patients, and the like) have become the builders of this representational universe. Moreover, by differentiating itself into a variety of social meanings depending on space and time, this plural universe gives rise to different types of social, economic and legal issues that engender ambiguity and make the analyst’s work diffcult. Consequently, in analyzing medications, the tendency is generally to break up the pathway they follow so that it is more accessible. Critics of biomedical models and supporters of the theory of complexity, such as Gatrell,2 Urry,3 Thrift,4 Byrne,5 and Cilliers,6 suggest instead that healthcare and, along with it, the medication pathway, be considered in their complexity and holistically. We would thus avoid the reductionism of the compartmentalization posited by certain academic disciplines in particular. In a way, paradigms are being changed so that we can examine the processes and interactions that occur all along the medication pathway from the biomolecular mechanisms to the socio-institutional ones, without which epidemiological and clinical fndings cannot be placed in context.